CN103842340A - Nuclear transport modulators and uses thereof - Google Patents

Nuclear transport modulators and uses thereof Download PDF

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CN103842340A
CN103842340A CN201280047930.1A CN201280047930A CN103842340A CN 103842340 A CN103842340 A CN 103842340A CN 201280047930 A CN201280047930 A CN 201280047930A CN 103842340 A CN103842340 A CN 103842340A
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ring
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nitrogen
sulphur
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CN103842340B (en
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V·P·桑达纳亚卡
S·沙查姆
M·考夫曼
S·谢克特尔
D·麦考利
Y·兰德斯曼
W·塞纳佩迪斯
J-R·塞恩特-马丁
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Karyopharm Therapeutics Inc
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Abstract

The invention generally relates to nuclear transport modulators, e.g CRM1 inhibitors, and more particularly to a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula (I), or a pharmaceutically acceptable salt or composition thereof, e.g, in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.

Description

Nuclear translocation conditioning agent and application thereof
Related application
The U.S. Provisional Application that the application requires to submit on July 29th, 2011 U.S. Provisional Application is submitted at number on July 29th, 61/513,428,2011 number 61/513,432, and the rights and interests of the U.S. Provisional Application of submitting on May 31st, 2012 number 61/653,588.In full the content of application is above combined in to this with it by reference.
Background of invention
The cell of most of main human entity and Malignancy presents the people such as the abnormal cellular localization (Cronshaw(Krona is desolate) of multiple tumorigenesis albumen, tumor suppressor protein and the cell cycle regulating factor, Buddhist nun in 2004, Falini(richness) etc. people 2006).For example, some p53 sudden change can cause cell matrix location, but not nucleus location.This has caused the disappearance of normal growth regulation and control, although tumor suppression function is complete.In other tumours, wild type p53 is isolated in tenuigenin tenuigenin or is degraded rapidly, again causes the forfeiture of the inhibitor function of this wild type p53.The recovery of the appropriate nucleus location of functional p53 albumen, can make the people such as some characteristic normalizings (Cai(Cai) of tumour cell, 2008; Hoshino(star open country) etc. people, 2008; Lain(Lay grace) etc. people, 1999a; Lain(Lay grace) etc. people, 1999b; Smart(Si Mate) etc. people, 1999), can recover the people such as the susceptibility (Cai(Cai) of cancer cells to DNA damage reagent, 2008), can cause degeneration (Sharpless(Sharpless) the & DePinho(Di Feiou of the tumour growing up to) 2007, Xue Xue() etc. people, 2007).From other tumor suppressor proteins as jaw (forkhead) (Turner(Tener) and Sullivan(Su Liwen) 2008) and c-Abl(Vignari(Wigner auspicious) and Wang(king) 2001) also obtained similar data.In addition, the abnormal location of some tumor-inhibiting factor and adjusting and controlling growth albumen may (Davis(Davis) 2007 relevant to the pathogeny of autoimmune disorder, Nakahara(Central Plains) 2009).CRM1 suppresses in familial cancer syndrome, (for example to provide significant especially application, Li-Fraumeni(Li-the Fo Meini being caused by a p53 deletion allele) syndrome, BRCA1 or BRCA2 cancer syndrome), wherein special tumor suppressor protein (TSP) is eliminated or has dysfunction, and wherein the raising of the TSP level realizing of (or local) the CRM1 supressor by system can help to recover normal tumor suppression function.
Special albumen and RNA input or output nucleus by special transport molecule, if molecule is inputted nucleus by they, this is classified as input albumen, if molecule is exported nucleus by they, are classified as the people such as output albumen (in Terry(spy), 2007; Sorokin(Sorokin) etc. people 2007).Be transfused to or export nuclear protein and comprise core input/location (NLS) or core output (NES) sequence, make they and relevant transport factor interaction.Chromosomal region stabilize proteins 1(Crm1 or CRM1), also referred to as output albumen-1 or Xpo1, be main output albumen.
According to report, in several tumours, Crm1 crosses expression, these tumours comprise the people such as human ovarian carcinoma (Noske(Nuo Sike), 2008), the people such as cervical cancer (van der Watt(Fan Dewa), 2009), the people such as carcinoma of the pancreas (Huang(Huang), 2009), the people such as liver cancer (Pascale(pascal Lay), 2005) and the people such as osteogenic sarcoma (Yao((Yao), 2009), and Crm1 cross express independently interrelated with the poor clinical effectiveness of these tumor types.
The inhibition blocking-up tumor suppressor protein of Crm1 and/or growth regulatory factor are as the core output of p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or jaw albumen (as FOXO3a), and this core output is relevant to genetic expression, cell proliferation, vasculogenesis and Epigenetics.There is result to show the apoptosis that Crm1 supressor can inducing cancer cell, or even in the situation that carcinogenic activation signal or growth actuation signal exist, and do not affect normal (not being converted) cell.Natural product Crm1 supressor leptomycin B (LMB) has been applied in the research that great majority suppress about Crm1.LMB itself has very high toxicity to tumour cell, but is difficult to by the people such as animal (Roberts(Luo Baici), 1986 because of significant gastrointestinal toxicity) and the people such as people (Newlands(Niu Lanzi), 1996) acceptance.Derivative LMB improves that class medicine characteristic can obtain not only can retaining anti-tumor activity also but also can be by the better people such as compound (Yang(poplar) of tolerance of animal tumor model, 2007, Yang(poplar) etc. people, 2008, Mutka(Mut card) etc. people, 2009).Therefore, core output supressor can have beneficial effect to neoplastic disease and other proliferative diseases.
Except tumor suppressor protein, Crm1 also exports some key proteins relevant to numerous inflammatory process.These albumen comprise IkB, NF-kB, Cox-2, RXR α, Commd1, HIF1, HMGB1, FOXO, FOXP and other.Because can cause immunoglobulin (Ig) k(kappa) expression of gene and the nf kB(NF-kB/rel that gains the name) activating transcription factor of family, can regulate and control the expression of the mRNA of various and inflammation, propagation, gene that immunity is relevant with cells survival.Under basic condition, one is called the NF-kB albumen supressor of IkB, be combined, and IkB-NF-kB mixture makes the functional transcription inactivation of NF-kB in core with NF-kB.In the replying of inflammatory stimulus, IkB dissociates from IkB-NF-kB mixture, discharges NF-kB, recovers its potential transcriptional activity simultaneously.A lot of signals that activate NF-kB are exactly (phosphorylation of IkB can " mark " it carry out ubiquitination and proteolysis then) of accomplishing these by target IkB proteolysis.Core IkBa-NF-kB mixture can be outputed to tenuigenin by Crm1, this complex dissociation in tenuigenin, thus NF-kB is reactivated.The IkB of ubiquitination can also dissociate from NF-kB mixture, recovers the transcriptional activity of NF-kB.The inhibition of the output of inducing by the Crm1 in people neutrophil(e) cell and class scavenger cell (U937) of LMB not only causes the accumulation without the core IkBa-NF-kB mixture of transcriptional activity, also prevent initial NF-kB activation, or even under cytositimulation (Ghosh(Ghosh) 2008, Huang(Huang) 2000).In a different research, in pulmonary capillary endothelial cell, process and suppressed beta induced NF-kB DNA combination (first step of NF-kB transcriptional activation), IL-8 expression and intercellular adhesion molecule expression (the Walsh(Walsh) 2008 of IL-1 with LMB).COMMD1 is another supressor of NF-kB and both transcriptional activities of oxygen deficient induction factor 1 (HIF1).Can cause the increase (Muller(Muller) 2009 of the inhibition of the transcriptional activity to NF-kB and HIF1 by suppressing the core output of Crm1 blocking-up COMMD1).
Crm1 also mediates class xanthopsin X receptor alpha (RXR α) transhipment.RXR α expresses and play central role in regulation and control bile acide, cholesterol, lipid acid, steroid and xenobiotic metabolism and homeostasis at liver camber.In hepatitis, core RXR alpha levels significantly reduces, and mainly exports owing to the inflammation mediated RXR α core by Crm1.LMB can prevent that the kytoplasm of the beta induced RXR alpha levels of IL-1 in the sexual cell of people liver source from increasing (Zimmerman(Annemarie Zimmermann) 2006).
At NF-kB, the effect of the core output of Crm1 mediation in HIF-1 and RXR signal α shows to block core output for much having potential benefit across the inflammatory process of many tissues and organ, comprise vascular system (vasculitis, arteritis, polymyalgia rheumatica, arteriosclerosis), tetter (seeing below), rheumatosis (similar rheumatism and associated joint inflammation, psoriatic arthritis, spondyloarthropathy, Crystal Arthropathy, systemic lupus erythematous, mixed connective tissue disease, myositis, dermatomyositis, inclusion body myositis, undifferentiated connective tissue disease, sjogren syndrome, Xiu Gelianshi syndrome (Sjogren ' s syndrome), overlap syndrome etc.).
CRM1 suppresses to affect genetic expression as ICp27, E2F4, KLF5, YAP1 and ZAP by suppressing/activate a series of transcription factors.
Crm1 suppresses that a lot of Dermatology Department syndrome is had to potential result for the treatment of, comprises inflammatory dermatosis (allergy, allergic dermatitis, chemical dermatitis, psoriatic), sun damage (ultraviolet (UV) damage) and infects.With the most sufficient CRM1 inhibition of LMB research, normal keratinocyte is presented to minimum effect, and the keratinocyte under UV, TNF α or other inflammatory stimulus is presented to newly sea of anti-inflammatory activity (Kobayashi(holt) & Shinkai() 2005, Kannan(Ka Naan) & Jaiswal(Jie Siwo) 2006).Suppress Crm1 can also raise NRF2(nf red corpuscle system correlation factor 2) activity; wherein NRF2 can shielding angle keratinocyte cells (Schafer(Schaefer) etc. people; 2010; Kannan(Ka Naan) & Jaiswal(Jie Siwo) 2006) and the people such as other cell types (Wang(king), 2009) avoid oxidative damage.The apoptosis of the keratinization keratinocyte that LMB induction is infected as HPV16 by carinogenicity human papillomavirus (HPV) strain, but do not induce not the people such as the apoptosis of infected keratinocyte (Jolly(Qiao Li), 2009).
Crm1 also mediates the transhipment of crucial neuroprotective albumen, and these neuroprotective albumen can comprise that Parkinson (PD), alzheimer's disease and amyotrophic lateral sclerosis (ALS) are useful to neurodegenerative disease.For example; by (1) to crucial neuroprotective regulatory factor as NRF2(Wang(king) 2009), FOXA2(Kittappa(Kai Taba) etc. people; 2007) pressure core detention; be docked in neurocyte; and/or (2) realize the inhibition of the transcriptional activity of NFB by IB being isolated to the nucleus of neurogliocyte, Crm1 suppresses to slow down or to prevent the nerve cell death in these diseases.Also evidence suggests abnormal neurogliocyte propagation and extremely relevant (the Shen(Shen) 2008 of CRM1 level or CRM1 function).
The complete maturation of a lot of viruses also requires the complete core mainly being mediated by CRM1 to export.The virus that involves core output and/or CRM1 self in life cycle comprises human immunodeficiency virus (HIV), adenovirus, monkey I type retrovirus, berna disease virus, influenza virus (conventional strain and H1N1 and fowl H5N1 strain), hepatitis B virus (HBV) and hepatitis C virus (HCV), human papillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, Severe acute respiratory syndrome coronavirus, yellow fever virus, west nile virus, herpes simplex virus (HSV), cytomegalovirus (CMV), merkel's cells polyomavirus (MCV).(Bhuvanakantham(bar Wanke Pehanorm) 2010, Cohen(section is conspicuous) 2010, Whittaker(Wei Tekeer) 1998).Estimate, in the future, can find the virus infection of the complete core output of more dependences.
The output of passing through CRM1 output channel of the HIV transcript that contains Rev response element (RRE) RNA connecing with simple shear that impels not montage through kernel the HIV-1Rev albumen that shuttles back and forth in nucleus and tenuigenin.The inhibition of the rna transport of the Rev-mediation realizing as LMB or PKF050-638 by CRM1 supressor, can stop the transcription of HIV-1, suppress the generation of new HIV-1 virus particle, thereby reduce the level (Pollard(ripple rad) 1998 of HIV-1, Daelemans(Dai Lemanci) 2002).
Dengue fever virus (DENV) is common arthropod-borne virus disease singapore hemorrhagic fever (DF) and paathogenic factor more serious and potential fatal dengue hemorrhagic fever (DHF) thereof.DHF is seemingly by the excessively prosperous inflammatory response of DENV caused.NS5 is that the maximum of DENV is also the most conservative albumen.NS5 is from nucleus to cytoplasmic transhipment in CRM1 regulation and control, and wherein most of function of NS5 is mediated.Suppress the output of the NS5 of CRM1 mediation, dynamic (dynamical) change that can cause virus to generate, reduce the induction of inflammatory chemokine interleukin 8 (IL-8), for treatment DENV and other medically important flavivirus comprise that the disease that hepatitis C virus causes provides a new approach (Rawlinson(Luo Linsen) 2009).
Other rna binding proteins that use CRM1 to export nuclear encoding viral comprise HSV I type tegument protein (VP13/14 or hUL47), people CMV albumen pp65, sars coronavirus ORF3b albumen and RSV matrix (M) albumen (Williams(WILLIAMS-DARLING Ton) 2008, Sanchez(Sang Qiesi) 2007, Freundt(Fleder) 2009, Ghildyal(Ji You Dell) 2009).
What is interesting is, much these viruses are relevant to the human cancer of particular type, and these cancers comprise by Chronic HBV or HCV and infect the liver cancer (HCC) causing, the relevant merkel's cells cancer of cervical cancer, MCV that HPV causes.Therefore the carcinous conversion process that CRM1 supressor causes virus infection and these virus is all useful.
CRM1 controls nucleus location, thereby controls the activity of multiple DNA metabolic enzymes, and these enzymes comprise histone deacetylase (HDAC), histone acetyltransferase (HAT), ZNFN3A1 (HMT).Be proved to be and be recognized that, irreversible CRM1 supressor is relevant to the core detention (and activation) of HDAC5 to the inhibition of cardiac myocyte hypertrophy, wherein HDAC5 is the people such as enzyme (Monovich(Mo Naweiqi) of the loose genetic program of a known inhibition, 2009).Therefore, CRM1 suppresses can be to loose syndrome, comprises congestive heart failure and the hypertrophic neuropathy of particular form, has beneficial effect.
CRM1 is also relevant to other diseases.A kind of degeneration take retinal ganglial cells and visual deprivation are the genetic diseases-Leber disease of feature (Leber ' s disorder) and invalid relevant (2008) of CRM1 switch.Also evidence suggests, nerve degenerative diseases is relevant to abnormal nucleus transhipment.
But so far, still uncommon for the micromolecular class medicine Crm1 supressor of in vitro and in vivo.
Summary of the invention
The present invention relates to be useful on compound or its pharmacy acceptable salt as nuclear translocation conditioning agent.The present invention also provides the pharmaceutically acceptable composition that comprises compound of the present invention, and uses described compound abnormal cellss disorderly as that to improperly core transportation trigger different from composition treatment to react relevant disorder or the method for the patient's condition.
In one embodiment of the invention, these are that useful compound is to be represented by formula I as core transportation conditioning agent:
Figure BDA0000484103910000071
Or its pharmacy acceptable salt, wherein, each variable be as defined herein with describe.
An alternative embodiment of the invention is a kind of composition, and said composition comprises a kind of compound of the present invention, or its a kind of pharmacy acceptable salt, and a kind of pharmaceutically acceptable carrier.
Another embodiment again of the present invention is a kind of being used for the treatment of and the method for the active associated a kind of disorder of CRM1, and the method comprises to the experimenter who it is had to needs and gives a kind of compound of the present invention or its a kind of pharmacy acceptable salt or a kind of composition that comprises compound of the present invention or its pharmacy acceptable salt for the treatment of significant quantity.
An alternative embodiment of the invention is the purposes that compound of the present invention is used for the treatment of a kind of disorder associated with CRM1 activity in a subject.
An alternative embodiment of the invention is the purposes of a kind of compound of the present invention for the manufacture of a kind of medicine, and this medicine is used for the treatment of one disorder associated with CRM1 activity in a subject.
Core of the present invention transportation conditioning agent and its pharmacy acceptable salt and/or composition provide in excellent body and have exposed to the open air, as measured in mouse, rat, dog and monkey by AUC, have represented low-level brain infiltration simultaneously.Therefore disease, disorder or illness (those diseases, disorder or the patient's condition as described here) that, compound of the present invention and pharmacy acceptable salt thereof and/or composition react relevant for the multiple abnormal cells triggering to core transportation improperly for the treatment of are useful.The research being regulated for the core transportation in biology and pathology phenomenon by compound provided by the invention; By the research of kinase mediated intracellular signal transduction path; And the comparative evaluation of core transportation conditioning agent is also useful.
Brief Description Of Drawings
Fig. 1 is as the figure of the mean tumour volume of the function of time and has shown (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) impact of-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone (compound 1) on gross tumor volume in the mouse xenograft tumor model of HCT-116.
Fig. 2 A is the image of western blotting, and be presented at process with compound 1 before and different time afterwards, from p53, p21, total length (FL) PARP and the PARP of cracking and the amount of lamin B in the protein extract of the tenuigenin part of HCT-116 cell.
Fig. 2 B is the image of western blotting, and be presented at process with compound 1 before and different time afterwards, from p53, p21, total length (FL) PARP and the PARP of cracking and the amount of lamin B in the protein extract of the core part of HCT-116 cell.
Fig. 3 A is the image of western blotting, and be presented at process with compound 1 before and different time afterwards, from pRb, the pRB(pRb of phosphorylation in the protein extract of the tenuigenin part of HCT-116 cell phos) and the amount of lamin B.
Fig. 3 B is the image of western blotting, and be presented at process with compound 1 before and different time afterwards, from pRb, the pRB(pRb of phosphorylation in the protein extract of the core part of HCT-116 cell phos) and the amount of lamin B.
Fig. 4 A is the figure as the EAE score of the function of time, and the impact of the compound 1 of having shown different amounts on the EAE score in the EAE model of multiple sclerosis.
Fig. 4 B is the figure as the body weight of the function of time, and the impact of the compound 1 of having shown different amounts on the body weight in the EAE model of multiple sclerosis.
Fig. 5 shows the result in the lymphocytic FACS classification of the mouse subgroup of the 26th day for EAE model described herein.
Detailed description of the invention
According to the inspection of following detailed explanation of the present invention, it is clear that the feature of novelty of the present invention will become for the ordinary skill in the art.But, should be understood that, although pointed out some embodiment of the present invention, detailed description of the present invention and the specific examples providing thereof only provide as illustrative object, this is because from detailed description of the present invention and claims below, and different change within the spirit and scope of the present invention or modification will become clear for the ordinary skill in the art.
Definition
Compound of the present invention is included in those that above describe generally, and further describes by classification disclosed here, subclass and kind.As used herein, except as otherwise noted, should use definition below.For all objects of the present invention, these chemical elements are according to the periodic table of elements, CAS version, physical chemistry handbook, the 75th edition (Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed) identify.In addition, vitochemical rule is described in " Organic Chemistry(organic chemistry) ", Thomas Sorrell(thomas Soret that), the University Science Books(book publishing society that studies science greatly), Suo Salituo: 1999, and " March ' the strange Advanced Organic Chemistry of s Advanced Organic Chemistry(horse) ", the 5th edition, Smith(Smith), M.B. strange with March(agate), J. compile, John Wiley & Sons(John Willie father and son publishing company), New York: in 2001, their full content is combined in to this by reference.
Within this specification sheets unless otherwise indicated, the nomenclature using is in this manual followed generally in Nomenclature of Organic Chemistry(organic chemistry nomenclature), A, B, C, D, E, F and H chapters and sections, Pergamon Press(Pergamum press), Oxford, example and the rule of explanation in 1979, for its exemplary chemical structure name and the rule of naming about chemical structure, be combined in this by reference by it.Optional, can use a kind of chemical name program (ACD/ChemSketch, September 5.09 editions/calendar year 2001, Advanced Chemistry Development, Inc.(Gao Deng chemical developer company limited), Canada, Toronto) produce the title of compound.
Compound of the present invention can have asymmetric center, chiral axis and chirality plane are (for example, as be described in E.L.Eliel(Yi Laier) with the human relations of S.H.Wilen(prestige) work, the stereochemistry of Stereo-chemistry of Carbon Compounds(carbon compound), John Wiley & Sons(John Willie father and son publishing company), New York, 1994, 1119-1190 page), and as raceme, racemic mixture and single diastereomer or enantiomer exist, wherein whole possible isomer and composition thereof (comprising optically active isomer) comprise in the present invention.
As term used herein " aliphatic " or " aliphatic group " refer to a kind of univalence hydrocarbyl, this alkyl is straight chain (being non-side chain), side chain or ring-type (comprise condense, many rings bridging and spiro-condensed).A kind of aliphatic group can be saturated or comprise one or more unsaturated but be not aromatic unit.Unless otherwise indicated, aliphatic group comprises 1-6 carbon atom.But in certain embodiments, an aliphatic group comprises 1-10 or 2-8 carbon atom.In certain embodiments, aliphatic group comprises 1-4 carbon atom, and in other other embodiment, aliphatic group comprises 1-3 carbon atom.Applicable aliphatic group includes but not limited to that alkyl straight chain or side chain, thiazolinyl and alkynyl and hybrid thereof are as (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.
If term used herein " alkyl " meaning is a kind of aliphatic group of saturated, straight chain or side chain.In one aspect, an alkyl comprises 1-10 or 2-8 carbon atom.Alkyl is including but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl and analogue.
If term used herein " thiazolinyl " meaning is aliphatic group a kind of straight chain or side chain, this group has one or more carbon-carbon double bonds (-CH=CH-).In one aspect, a thiazolinyl has from two to eight carbon atoms, and comprises, such as, but not limited to this vinyl, 1-propenyl, 1-butylene base and analogue.Term " thiazolinyl " include have in " cis " and " trans " or the group with the carbon-carbon double bond of " Z " conformation in " E " alternately.If a thiazolinyl comprises more than one carbon-carbon double bond, each carbon-carbon double bond is a kind of cis or trans double bond independently, or its a kind of mixture.
If term used herein " alkynyl " meaning is aliphatic group a kind of straight chain or side chain, this group has one or more carbon carbon triple bonds (-C ≡ C-).In one aspect, an alkyl has from two to eight carbon atoms, and comprises, such as, but not limited to this 1-proyl (propargyl), ethyl acetylene base and analogue.
That use separately or refer to a kind of saturated or loop systems of undersaturated annular aliphatic monocycle or dicyclo partly as term " alicyclic ", " carbocylic radical ", " carbocyclic ring " and " carbocyclic ring type " of the part of a greater part, have as described in this from 3 to 10 members, wherein as this aliphatics loop systems defined above and explanation herein is optionally substituted.In certain embodiments, an alicyclic group has 3-6 carbon atom.Alicyclic group includes, without being limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl, cycloheptenyl, ring octyl group, cyclooctene base and cyclooctadiene base.Term " alicyclic ", " carbocylic radical ", " carbocyclic ring " and " carbocyclic ring type " also comprise aliphatic ring, these rings are fused to the ring of one or more aromatic or non-aromatics, as ten ammonia naphthyls, tetralyl, naphthane or two ring [2.2.2] octanes.
If term used herein " cycloalkyl " meaning is a kind of saturated loop systems annular aliphatic monocycle or dicyclo, this loop systems has from 3-10 member.A kind of cycloalkyl is as explanatorily can being optionally substituted at this.In certain embodiments, a cycloalkyl has 3-6 carbon.
Term " Heterocyclylalkyl " meaning is a kind of saturated or unsaturated aliphatic loop systems as used in this, and wherein at least one carbon atom is replaced by a heteroatoms that is selected from N, S and O.A Heterocyclylalkyl can comprise one or more rings, and this ring can be attached together or can condense in a kind of mode poising.In one aspect, Heterocyclylalkyl be one three-to the loop systems of seven-unit, and comprise, such as, but not limited to this piperidyl, piperazinyl, pyrrolidyl, tetrahydrofuran base and analogue.
Term " heteroatoms " refers to one or more in oxygen, sulphur, nitrogen, phosphorus or silicon the form of any oxidation that comprises nitrogen, sulphur, phosphorus or silicon; The quaternised form of the nitrogen of any alkalescence; And the commutable nitrogen of a heterocycle, for example N(is as in 3,4-dihydro-2 h-pyrrole base), NH(is as in pyrrolidyl) or NR +(in the pyrrolidyl replacing at N-).
Term " undersaturated " refers to the part with one or more unsaturated units as used herein.
As used herein, refer to-O-of term " alkoxyl group " alkyl." alkoxyl group " can comprise alkyl a kind of straight chain or side chain.In one aspect, " alkoxyl group " has from one to eight carbon atom, and comprises, such as, but not limited to this methoxyl group, oxyethyl group, propoxy-, isopropoxy, t-butoxy and analogue.
Term " halo (halo) " or " halogen (the halogen) " meaning is the halogen in radioactive and inactive form as used herein, and comprises, and for example, but is not limited to this fluorine, chlorine, bromine, iodine etc.
Term " alkylhalide group " refers to a kind of alkyl being replaced by one or more halogen atoms as used herein.In certain embodiments, alkylhalide group refers to a kind of fully halogenated alkyl.In certain embodiments, alkylhalide group refers to a kind of alkyl being replaced by one or more halogen atoms.Comprise-CF of exemplary alkylhalide group 3,-CCl 3,-CF 2cH 3,-CH 2cF 3,-CH 2(CF 3) 2,-CF 2(CF 3) 2, and analogue.
Term " alkylidene group " means a kind of saturated hydrocarbyl side chain or non-side chain of divalence as used herein.In one aspect, " alkylidene group " has one to eight carbon atom, and comprises, such as, but not limited to this methylene radical, ethylidene, n-propylidene, n-butylidene and analogue.
If term used herein " alkenylene " meaning is a kind of alkyl side chain or non-side chain of divalence, this alkyl has one or more carbon-carbon double bonds (-CH=CH-).In one aspect, " alkenylene " has two to eight carbon atoms, and comprises, such as, but not limited to this vinylidene, n-propenylidene, n-crotonylidene and analogue.
If term used herein " alkynylene " meaning is a kind of alkyl side chain or non-side chain of divalence, this alkyl has one or more carbon carbon triple bonds (-C ≡ C-).In one aspect, " alkynylene " has two to eight carbon atoms, and comprises, such as, but not limited to this sub-proyl of ethynylene, n-, n-butynelene and analogue.
The term " aryl " being used alone or in combination at this refers to a kind of carbocyclic ring aroma system, and this system comprises one or more rings, and this ring can be attached together or can condense in a kind of mode poising.In specific embodiment, aryl is one, two or three rings.On the one hand, this aryl has 5 to 12 annular atomses.Term " aryl " comprises aromatic group, as phenyl, naphthyl, tetralyl, indanyl, xenyl, phenanthryl, anthryl and acenaphthenyl (acenaphthyl).A kind of " aryl " group can have 1 to 4 substituting group, as low alkyl group, hydroxyl, halogen, alkylhalide group, nitro, cyano group, alkoxyl group, lower alkyl amino etc.
Term " heteroaryl " the alone or in combination meaning is a kind of aroma system as used in this, and the heteroatoms that wherein at least one carbon atom is selected from N, S and O replaces.A heteroaryl can comprise one or more rings, and this ring can be attached together or can condense in a kind of mode poising.In specific embodiment, heteroaryl is one, two or three rings.On the one hand, this heteroaryl has 5 to 12 annular atomses.Term " heteroaryl " comprises heteroaryl group, as triazolyl, imidazolyl, pyrryl, pyrazolyl, tetrazyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl and analogue.A kind of " heteroaryl " group can have 1 to 4 substituting group, as low alkyl group, hydroxyl, halogen, alkylhalide group, nitro, cyano group, alkoxyl group, lower alkyl amino etc.
Should be understood that substituting group and substitute mode on compound of the present invention can be selected by an one skilled in the relevant art, thereby provide compound, these compounds are chemically stable, and are easy to by technology as known in the art and those methods of below enumerating synthetic.Conventionally, no matter whether, by " optionally " face before it, one or more hydrogen that term " substituted " refers to specified portions is substituted by suitable substituting group.Except as otherwise noted, a kind of " optionally substituted " group can have a kind of suitable substituting group on the each commutable position of this group, and in any given structure, in the time that more than one position is replaced by the more than one substituting group that is selected from a kind of group indicating, can be same or different at the substituting group of each position.Alternately, a kind of " optionally substituted " group can not replace.
The substituent combinatorial optimization ground that the present invention considers is that those results are to form stable or chemically feasible compound.If a kind of substituting group itself is replaced by more than one group, should be understood that these multiple groups can be on same carbon atom or on different carbon atoms, as long as result is to obtain a kind of stable structure.Term " stable " refers to such compound as used herein, when standing their production, the condition that detection is allowed, and in certain embodiments, their recovery, purifying and during for one or more object disclosed here, they do not change substantially.
Suitable unit price substituting group on the substitutable carbon atom of " optionally substituted " group is independently: halogen;-(CH 2) 0-4r °;-(CH 2) 0-4oR °;-O (CH 2) 0-4r ° ,-O-(CH 2) 0- 4c (O) OR °;-(CH 2) 0-4cH (OR °) 2;-(CH 2) 0-4sR °;-(CH 2) 0-4ph, it can be by R ° of replacement;-(CH 2) 0-4o (CH 2) 0-1ph, it can be by R ° of replacement;-CH=CHPh, it can be by R ° of replacement;-(CH 2) 0- 4o (CH 2) 0-1-pyridyl its can be by R ° of replacement;-NO 2;-CN;-N 3;-(CH 2) 0-4n (R °) 2;-(CH 2) 0- 4n (R °) C (O) R °;-N (R °) C (S) R °;-(CH 2) 0-4n (R °) C (O) NR ° 2;-N (R °) C (S) NR ° 2;-(CH 2) 0-4n (R °) C (O) OR °;-N (R °) N (R °) C (O) R °;-N (R °) N (R °) C (O) NR ° 2;-N (R °) N (R °) C (O) OR °;-(CH 2) 0-4c (O) R °;-C (S) R °;-(CH 2) 0- 4c (O) OR °;-(CH 2) 0- 4c (O) SR °;-(CH 2) 0-4c (O) OSiR ° 3;-(CH 2) 0-4oC (O) R °;-OC (O) (CH 2) 0-4sR-, SC (S) SR °;-(CH 2) 0-4sC (O) R °;-(CH 2) 0-4c (O) NR ° 2;-C (S) NR ° 2;-C (S) SR °;-SC (S) SR ° ,-(CH 2) 0-4oC (O) NR ° 2;-C (O) N (OR °) R °;-C (O) C (O) R °;-C (O) CH 2c (O) R °;-C (NOR °) R °;-(CH 2) 0-4sSR °;-(CH 2) 0-4s (O) 2r °;-(CH 2) 0- 4s (O) 2oR °;-(CH 2) 0-4oS (O) 2r °;-S (O) 2nR ° 2;-(CH 2) 0-4s (O) R °;-N (R °) S (O) 2nR ° 2;-N (R °) S (O) 2r °;-N (OR °) R °;-C (NH) NR ° 2;-P (O) 2r °;-P (O) R ° 2;-OP (O) R ° 2;-OP (O) (OR °) 2; SiR ° 3;-(C 1-4the alkylidene group of straight or branched) O-N (R °) 2; Or-(C 1-4the alkylidene group of straight or branched) C (O) O-N (R °) 2, wherein each R ° can be substituted as below defined and be hydrogen independently, C 1-6aliphatic ,-CH 2ph ,-O (CH 2) 0-1ph ,-CH 2-(hetero-aromatic ring of 5-6 unit), or have 0-4 independently selected from the heteroatomic 5-6-unit of nitrogen, oxygen and sulphur saturated, the ring of the undersaturated or aryl of part, or, although there is definition above, but two independent R ° of occurring one or more insertion atoms together with them form one have 0-4 heteroatomic 3-12-unit independently selected from nitrogen, oxygen and sulphur saturated, rings monocycle or two rings of the undersaturated or aryl of part, it can be as below defined and be substituted.
Suitable unit price substituting group on R ° (or by two independent R ° of rings that form together with their insertion atom that occur) is halogen independently ,-(CH 2) 0- 2r ●,-(halo R ●) ,-(CH 2) 0-2oH ,-(CH 2) 0- 2oR ●,-(CH 2) 0-2cH (OR ●) 2;-O (halo R ●) ,-CN ,-N 3,-(CH 2) 0-2c (O) R ●,-(CH 2) 0-2c (O) OH ,-(CH 2) 0-2c (O) OR ●,-(CH 2) 0-2sR ●,-(CH 2) 0-2sH ,-(CH 2) 0- 2nH 2,-(CH 2) 0-2nHR ●,-(CH 2) 0-2nR ● 2,-NO 2,-SiR ● 3,-OSiR ● 3,-C (O) SR ●,-(C 1-4the alkylidene group of straight or branched) C (O) OR ●, or-SSR ●wherein each R ●not being substituted or before it, having the situation of " halo (halo) " is only to be replaced by one or more halogens, and independently selected from C 1-4aliphatic ,-CH 2ph ,-O (CH 2) 0-1ph, or have independently selected from the 0-4 of nitrogen, oxygen and sulphur heteroatomic 5-6-unit saturated, the ring of the undersaturated or aryl of part.Comprise=the O of substituting group of the suitable divalence on the saturated carbon atom of R and=S.
These below the substituting group of the suitable divalence on the saturated carbon atom of " optionally substituted " group comprises :=O ,=S ,=NNR * 2,=NNHC (O) R *,=NNHC (O) OR *,=NNHS (O) 2r *,=NR *,=NOR *,-O (C (R * 2)) 2-3o-, and-S (C (R * 2)) 2-3s-, wherein, each self-existent R *be selected from hydrogen, can be as the substituted C below defining 1-6aliphatic, or one have 0-4 independently selected from the heteroatomic unsubstituted 5-6 unit of nitrogen, oxygen and sulphur saturated, part is undersaturated or the ring of aryl.The substituting group that is attached to the suitable divalence on the commutable carbon on the ortho position of " optionally substituted " group comprises :-O (CR * 2) 2-3o-, wherein, each self-existent R *be selected from hydrogen, can be as the substituted C below defining 1-6aliphatic, or one have 0 to 4 independently selected from nitrogen, oxygen and sulphur heteroatomic unsubstituted 5 to 6 yuan saturated, part is undersaturated or the ring of aryl.
At R *fatty group on suitable substituting group comprise halogen ,-R ●,-(halo R ●) ,-OH ,-OR ●,-O (halo R ●) ,-CN ,-C (O) OH ,-C (O) OR ●,-NH 2,-NHR ●,-NR ● 2, and-NO 2, wherein each R ●be unsubstituted or before it, to have the situation of " halo " be only to be replaced by one or more halogens, and be C independently 1-4aliphatic ,-CH 2ph ,-O (CH 2) 0-1ph, or a kind of have independently selected from the 0-4 of nitrogen, oxygen or sulphur heteroatomic 5-6-unit saturated, the ring of the undersaturated or aryl of part.
Suitable substituent on the replaced nitrogen of " optionally substituted " group comprises
Figure BDA0000484103910000161
Figure BDA0000484103910000162
Figure BDA0000484103910000163
with
Figure BDA0000484103910000164
wherein each
Figure BDA0000484103910000165
hydrogen independently, can be as below defined substituted C 1-6aliphatic, unsubstituted-OPh, or have 0-4 independently selected from the heteroatomic unsubstituted 5-6-unit of nitrogen, oxygen and sulphur saturated, the ring of the undersaturated or aryl of part, or, although there are definition above, two independent generations
Figure BDA0000484103910000171
together with their one or more insertion atoms form one have 0-4 independently selected from the heteroatomic unsubstituted 3-12-unit of nitrogen, oxygen and sulphur saturated, rings monocycle or two rings of the undersaturated or aryl of part.
?
Figure BDA0000484103910000172
fatty group on suitable substituting group be halogen independently ,-R ●,-(halo R ●) ,-OH ,-OR ●,-O (halo R ●) ,-CN ,-C (O) OH ,-C (O) OR ●,-NH 2,-NHR ●,-NR ● 2, or-NO 2, wherein each R ●be unsubstituted or before it, to have the situation of " halo " be only to be replaced by one or more halogens, and be C independently 1-4aliphatic ,-CH 2ph ,-O (CH 2) 0- 1ph, or a kind of have independently selected from the 0-4 of nitrogen, oxygen or sulphur heteroatomic 5-6-unit saturated, the ring of the undersaturated or aryl of part.
As used in this, term " pharmacy acceptable salt " means, within the scope of rational medical judgment, be suitable for contacting with the mankind and zootic tissue and there is no those salt of excessive toxicity, stimulation, anaphylaxis etc., match with rational benefit/risk ratio.These pharmacy acceptable salts are known in the art.For example, S.M.Berge(Berge) etc. people at J.Pharmaceutical Sciences(pharmaceutical science magazine), in 1977,66,1-19, describe these pharmacy acceptable salts in detail, be correlated with and teach content and be combined in this in full with it by reference.The pharmacy acceptable salt of compound of the present invention comprises derived from the suitable inorganic and organic salt of acid and alkali, these salt and patient's treatment compatibility.
Pharmaceutically acceptable, the example of nontoxic acid salt is a kind of and mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid, or organic acid form as acetic acid, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid or by the amino salt that uses other the method using in the art to form as ion-exchange.Other pharmaceutically acceptable acid salt comprises adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cipionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, sulfuric acid bay salt, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin salt, persulphate, 3-phenpropionate, phosphoric acid salt, pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, p-toluenesulfonic esters, undecylate, valerate etc.
In certain embodiments, the exemplary mineral acid that forms suitable salt includes but not limited to, hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid and acid metal salt are as Sodium phosphate dibasic and sal enixum.The illustrative organic acid that forms suitable salt comprises monocarboxylic acid, two carboxylic acid and tricarboxylic acid.Illustrative this type of acid is, for example, acetic acid, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, phenylformic acid, hydroxy-benzoic acid, toluylic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid, p-methyl benzenesulfonic acid and other sulfonic acid are as methylsulfonic acid and 2-ethylenehydrinsulfonic acid.Can form single-or the salt of two-acid, and this type of salt can with hydration, solvate or substantially anhydrous form exist.Conventionally, the acid salt of these compounds is compared with their free alkali form, is more easily molten, and has conventionally shown higher fusing point in water and in different hydrophilic organic solvents.
In certain embodiments, have that the acid salt of compound of formula I is the most applicable to be formed from pharmaceutically acceptable acid, and comprise, for example, those and mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid and organic acid, for example succsinic acid, toxilic acid, acetic acid or fumaric acid form.
Other non-pharmacy acceptable salt, for example oxalate can be for for example for using in laboratory, or for the segregation of the compound with formula I of the conversion to a kind of pharmaceutically acceptable acid salt subsequently.Within the solvate of base addition salt (as sodium, potassium and ammonium salt), compound of the present invention and hydrate are also included within scope of the present invention.Can complete the conversion from a kind of salt of given compound to a kind of salt of compound of hope by the standard technique known of application those skilled in the art.
A kind of " pharmaceutically acceptable base addition salt " is any nontoxic, organic or inorganic base addition salt of these acidic cpds of through type I representative, or its any intermediate.The exemplary mineral alkali that forms suitable salt includes but not limited to, the oxyhydroxide of lithium, sodium, potassium, calcium, magnesium or barium.The exemplary organic bases that forms suitable salt comprises, aliphatic, alicyclic or aromatic organic amine, as methylamine, Trimethylamine and picoline or ammonia.The selection of suitable salt may be important, and it is unhydrolyzed making the elsewhere of ester functionality (if any) in molecule.Choice criteria for suitable salt is that those skilled in the art know.
Comprise basic metal, alkaline-earth metal, ammonium and N derived from the salt of suitable alkali +(C 1-4alkyl) 4salt.Representational alkali or alkaline-earth metal salt comprise sodium, lithium, potassium, calcium, magnesium etc.In addition pharmacy acceptable salt comprises, in appropriate circumstances, nontoxic ammonium, quaternary ammonium and use counter ion as the amine positively charged ion of halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, the alkylsulfonate such as low and aryl sulfonic acid salt formation.
Unless otherwise specified, the structure of describing at this also means all isomeric (for example, enantiomer, diastereomer and geometric (or conformation)) form that comprises this structure; For example, the R to each asymmetric center and S configuration, Z and E double bond isomer, and Z and E conformer.Therefore, mixture within the scope of the present invention together with enantiomer, diastereomer and geometric (or conformation) for the single stereochemical isomers of these compounds.Unless otherwise specified, all tautomeric forms of compound of the present invention within the scope of the present invention.
In addition, unless otherwise specified, the structure of describing at this also means and comprises, difference is only these compounds of the atom that has one or more isotopic enrichments.For example, by by deuterium or tritium instead of hydrogen, or with a kind of 13c-or 14the carbon of C-enrichment substitute that carbon produces compound within the scope of the invention.This compounds conduct, for example, the instrument of analysis, the probe in biology is measured, or be useful according to therapeutical agent of the present invention.
Term " steric isomer " is a general term, for all isomer of the individual molecule that only orientation in space is different at their atom.It comprises mirror image isomer (enantiomer), how much (cis/trans) isomer and has an isomer (diastereomer) that does not become each other above the compound of the chiral centre of mirror image.
Term " pharmaceutically acceptable carrier " refers to mixing with this activeconstituents of a kind of nontoxic solvent, dispersion agent, vehicle, adjuvant or other so that allow the material of the formation of medicinal compositions (that is, can give the formulation of patient's medication).An a kind of like this example of carrier is typically used in the pharmaceutically acceptable oil of parenteral admistration.These pharmaceutically acceptable carriers are known in the art.
In the time introducing key element disclosed here, article "/one (a/an) ", " being somebody's turn to do (the) " and " described (said) " are intended to show to have one or more this key element.Term " comprises (comprising) ", " having (having) " and " comprising (including) " to be intended to be open, means other elements that can exist beyond the element of listing.
Compound of the present invention
One embodiment of the present of invention are a kind of compounds that represented by formula I:
Figure BDA0000484103910000201
Or its a kind of pharmacy acceptable salt, wherein:
Ring A is selected from optionally substituted ring of following one: phenyl, 8-10-unit aryl bicyclic ring, has independently selected from 1-4 heteroatomic 5-6-unit's monocycle hetero-aromatic ring of nitrogen, oxygen and sulphur and has the heteroatomic 8-10-of independently selected from nitrogen, oxygen and sulphur 1-4 unit two ring hetero-aromatic rings;
Ring B is an optionally substituted ring, this ring is selected from the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur;
X is selected from O, S, N-CN and NR;
R is hydrogen or is a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, have independently selected from the 1-2 of nitrogen, oxygen and sulphur heteroatomic 3-8 unit saturated or the ring of undersaturated heterocycle partly, phenyl, and there is the heteroatomic 5-6 of independently selected from nitrogen, oxygen and sulphur 1-4 unit hetero-aromatic ring;
Y is the optionally C of substituted divalence of a covalent linkage or 1-4alkyl, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute;
R 1and R 2be hydrogen independently of one another or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, ring 3-8 unit, saturated or the undersaturated monocycle carbocyclic ring of part, phenyl, two cyclophane rings of 8-10 unit, there is the ring of 1-2 or part undersaturated monocyclic heterocycles unit, saturated independently selected from the heteroatomic 3-8 of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
R 1and R 2and insert form together with the atom between them a kind of have the heteroatomic 4-8 of independently selected from nitrogen, oxygen and sulphur 1-3 unit saturated, the ring of undersaturated or aromatic heterocycle partly, the ring quilt-(R wherein forming thus 5) preplace.
N, m and p are selected from an integer of 0,1,2,3 and 4;
Q is an integer, is selected from 0,1 and 2;
R 3, R 4, and R 5halogen ,-NO independently of one another 2,-CN ,-N 3,-L-R 6, or be selected from following optionally substituted group: C 1-6aliphatic group, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is 1-2 the ring independently selected from the saturated or undersaturated monocyclic heterocycles of part of the heteroatomic 3-8 unit of nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
Two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
Two R on ring A 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
By R 1and R 2two R on the ring forming 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them;
L is covalent linkage or the C of substituted divalence optionally 1-6alkyl, wherein, one or two methylene unit of L is optionally and independently by following substituting-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-;
-Cy-is an optionally substituted divalence ring, this ring is selected from a 3-7 unit, the saturated or undersaturated ring alkenylene of part ring, one have 1-4 independently selected from the heteroatomic 4-7 of nitrogen, oxygen and sulphur unit, the saturated or undersaturated heterocycle alkylene of part basic ring, phenylene, one has 1-4 the heteroarylidene independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, the arylidene of two rings of a 8-10 unit, and one have 1-4 the heteroarylidenes independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; And
Each R 6be hydrogen independently or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, ring 3-7 unit, saturated or the undersaturated carbocyclic ring of part, two ring fillings of 8-10 unit, the ring of the carbocyclic ring of undersaturated or aryl partly, there is the ring of 1-4 or part undersaturated heterocycle unit, saturated independently selected from the heteroatomic 4-7 of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; Or:
Two R on identical nitrogen 6and insert and form saturated, a undersaturated or aromatic heterocycle partly with 1-2 the heteroatomic 4-7 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them.
As described generally hereinbefore, ring A is selected from optionally substituted ring of following one: phenyl, 8-10-unit aryl bicyclic ring, has independently selected from 1-4 heteroatomic 5-6-unit's monocycle hetero-aromatic ring of nitrogen, oxygen and sulphur and has the heteroatomic 8-10-of independently selected from nitrogen, oxygen and sulphur 1-4 unit two ring hetero-aromatic rings.
In certain embodiments, ring A is substituted benzyl ring optionally.
In certain embodiments, ring A is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, ring A is substituted naphthyl ring optionally.
In certain embodiments, ring A has 1-4 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A has 1-4 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A has 1-3 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A has 1-2 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A has 3 hetero-aromatic rings independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A has 2 hetero-aromatic rings independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring A is the hetero-aromatic ring with 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 5-unit of 1-3 nitrogen-atoms.In certain embodiments, ring A is selected from optionally substituted group of following one: pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl group.
In certain embodiments, ring A is selected from:
Figure BDA0000484103910000241
In certain embodiments, ring A is:
Figure BDA0000484103910000242
In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, ring A is the hetero-aromatic ring with the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, ring A is selected from optionally substituted group of following one: pyridyl, pyrazinyl, pyridazinyl (pyridizinyl), pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, ring A is substituted pyridyl ring optionally.In certain embodiments, ring A is optionally substituted 1,6-pyridyl ring.In certain embodiments, ring A is:
Figure BDA0000484103910000251
As described generally hereinbefore, ring B is an optionally substituted ring, this ring is selected from the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur.
In certain embodiments, ring B is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, ring B is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, ring B is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
In certain embodiments, ring B is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, ring B is selected from optionally substituted cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclohexadienyl and cyclooctadiene base.
In certain embodiments, ring B is substituted benzyl ring optionally.
In certain embodiments, the benzyl ring that ring B is replaced by one or more groups independently selected from halogen, hydroxyl or trifluoromethyl.
In certain embodiments, ring B is by one or more optionally substituted methyl substituted phenyl.In certain embodiments, ring B is by a substituted methyl substituted phenyl optionally.In certain embodiments, ring B is by two substituted methyl substituted phenyl optionally.
In certain embodiments, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by least one halogen.In certain embodiments, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by least two halogens.In certain embodiments, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by least three halogens.
In certain embodiments, ring B is by one or more-CF 3the phenyl that group replaces.In certain embodiments, ring B is by two-CF 3the phenyl that group replaces.
In certain embodiments, ring B is:
Figure BDA0000484103910000261
In certain embodiments, ring B is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, ring B is substituted naphthyl optionally.
In certain embodiments, ring B has 1-2 the ring independently selected from the heterocycle of the saturated or undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, ring B is selected from optionally substituted '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base and homopiperazine base.
In certain embodiments, ring B has 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B is selected from optionally substituted aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, ring B has 1-4 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-4 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-3 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-2 the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 2 monocycle hetero-aromatic rings independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B is the monocycle hetero-aromatic ring with 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, ring B is selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl group.
In certain embodiments, ring B is the monocycle hetero-aromatic ring with the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, ring B is the monocycle hetero-aromatic ring with the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, ring B is the monocycle hetero-aromatic ring with the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, ring B is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, ring B is the monocycle hetero-aromatic ring with the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, ring B is optionally substituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or tetrazine base.
In certain embodiments, ring B is substituted pyridyl ring optionally.In certain embodiments, ring B is by one or more optionally substituted C 1-6the pyridyl ring that aliphatic group replaces.In certain embodiments, ring B is by one or more optionally substituted C 1-4the pyridyl ring that aliphatic group replaces.In certain embodiments, ring B is by one or more optionally substituted C 1-2the pyridyl ring that aliphatic group replaces.In certain embodiments, ring B is by one or more optionally substituted methyl substituted pyridyl ring.In certain embodiments, ring B is by one or more methyl substituted pyridyl ring, and this methyl is further replaced by one or more halogens.In certain embodiments, ring B is by one or more methyl substituted pyridyl ring, and this methyl is replaced by least one halogen.In certain embodiments, ring B is by one or more methyl substituted pyridyl ring, and this methyl is replaced by least two halogens.In certain embodiments, ring B is by one or more methyl substituted pyridyl ring, and this methyl is replaced by least three halogens.In certain embodiments, ring B is by one or more-CF 3the pyridyl ring that group replaces.In certain embodiments, ring B is by two-CF 3the pyridyl ring that group replaces.In certain embodiments, ring B is:
Figure BDA0000484103910000281
In certain embodiments, ring B has 1-4 the two ring hetero-aromatic rings independently selected from the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-3 the two ring hetero-aromatic rings independently selected from the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1-2 the two ring hetero-aromatic rings independently selected from the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B has 1 two ring hetero-aromatic ring independently selected from the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, ring B is optionally substituted benzofuryl, benzo thiophenyl, indyl, indazolyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl or cinnolines base.
As described generally hereinbefore, X is selected from O, S, N-CN and NR, and wherein R is hydrogen or is a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, have independently selected from the 1-2 of nitrogen, oxygen and sulphur heteroatomic 3-8 unit saturated or the ring of undersaturated heterocycle partly, phenyl, phenyl, and there is the heteroatomic 5-6 of independently selected from nitrogen, oxygen and sulphur 1-4 unit hetero-aromatic ring.
In certain embodiments, X is O.
In certain embodiments, X is S.
In certain embodiments, X is N-CN.
In certain embodiments, X is NR.More specifically, X is NH.Alternately, X is NCH 3.
As described generally hereinbefore, R is hydrogen or is a kind ofly selected from following optionally substituted group: C 1-6aliphatic, have independently selected from the 1-2 of nitrogen, oxygen and sulphur heteroatomic 3-8 unit saturated or the ring of undersaturated heterocycle partly, phenyl, and there is the heteroatomic 5-6 of independently selected from nitrogen, oxygen and sulphur 1-4 unit hetero-aromatic ring.
In certain embodiments, R is hydrogen.
In certain embodiments, R is substituted C optionally 1-6aliphatic.In certain embodiments, R is substituted C optionally 1-5aliphatic.In certain embodiments, R is substituted C optionally 1-4aliphatic.In certain embodiments, R is substituted C optionally 1-3aliphatic.In certain embodiments, R is substituted C optionally 1-2aliphatic.In certain embodiments, R is selected from optionally substituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, neo-pentyl, isopentyl, hexyl, vinyl, propenyl, butenyl, pentenyl, hexenyl or isobutenyl.
In certain embodiments, R has 1-2 the ring independently selected from the saturated or undersaturated heterocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 1-2 the ring independently selected from the saturated heterocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 2 rings independently selected from the saturated heterocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R is the ring with the saturated heterocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R is substituted '-aziridino (aziridinyl) optionally, Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base or homopiperazine base.
In certain embodiments, R has 1-2 the ring independently selected from the undersaturated heterocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 2 rings independently selected from the undersaturated heterocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R is the ring with the undersaturated heterocycle of part of 1 heteroatomic a kind of optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R is optionally substituted aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl or thiazolinyl.
In certain embodiments, R has 1-4 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 1-4 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 1-3 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 1-2 the hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R has 2 hetero-aromatic rings independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R is the hetero-aromatic ring with 1 heteroatomic a kind of optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R is selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl group, isoxazolyl, isothiazolyl, triazolyl and tetrazyl.
In certain embodiments, R is the hetero-aromatic ring with the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R is the hetero-aromatic ring with the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R is the hetero-aromatic ring with the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R is the hetero-aromatic ring with the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R is the hetero-aromatic ring with the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R is selected from optionally substituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl and tetrazine base.
In certain embodiments, X is NH.In certain embodiments, X is NCH 3.
As described generally hereinbefore, Y is the optionally C of substituted divalence of a covalent linkage or 1-4hydrocarbon chain, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.
In certain embodiments, Y is a covalent linkage.
In certain embodiments, Y is an optionally C for substituted divalence 1-4hydrocarbon chain, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, Y is an optionally C for substituted divalence 1-3hydrocarbon chain, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, Y is an optionally C for substituted divalence 1-2hydrocarbon chain, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.
In certain embodiments, Y is-O-.In certain embodiments, Y is-S-.In certain embodiments, Y is-N (R 6)-.In certain embodiments, Y be-C (O)-.In certain embodiments, Y be-C (O)-.In certain embodiments, Y is-NH-.In certain embodiments, Y is-CH 2o-.In certain embodiments, Y is-CH 2s-.In certain embodiments, Y is-CH 2n (H)-.
As described generally hereinbefore, R 1and R 2be selected from independently of one another hydrogen or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, ring 3-8 unit, saturated or the undersaturated monocycle carbocyclic ring of part, phenyl, two cyclophane rings of 8-10 unit, there is the ring of unit, the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 independently selected from nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur.
In certain embodiments, respectively hydrogen naturally of R1 and R2.In certain embodiments, R 1and R 2in one be hydrogen.
In certain embodiments, R1 is hydrogen.In certain embodiments, R 1substituted C optionally 1-6aliphatic.In certain embodiments, R 1substituted C optionally 1-5aliphatic.In certain embodiments, R 1substituted C optionally 1-4aliphatic.In certain embodiments, R 1substituted C optionally 1-3aliphatic.In certain embodiments, R 1substituted C optionally 1- 2aliphatic.In certain embodiments, R 1be selected from optionally substituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, neo-pentyl, isopentyl, hexyl, vinyl, propenyl, butenyl, pentenyl and hexenyl.
In certain embodiments, R 1it is substituted benzyl ring optionally.
In certain embodiments, R 1it is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, R 1it is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, R 1it is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, R 1be selected from optionally substituted cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclobutene base, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptenyl, cycloheptadiene base, ring octyl group, cyclooctene base and cyclooctadiene base.
In certain embodiments, R 1it is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 1it is substituted naphthyl ring optionally.
In certain embodiments, R 1to there is 1-2 the ring independently selected from the heterocycle of the saturated or undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there is 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there are 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1it is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 1to there is 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there are 2 rings independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1it is the ring with the heterocycle of the undersaturated monocycle of part of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 1be selected from optionally substituted '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, homopiperazine base, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base, aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyls (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 1to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 1be selected from optionally substituted pyrryl, furyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R 1it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R 1be selected from optionally substituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl and tetrazine base.
In certain embodiments, R 1to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 1be selected from optionally substituted indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
In certain embodiments, R 2hydrogen.In certain embodiments, R 2substituted C optionally 1-6aliphatic.In certain embodiments, R 2substituted C optionally 1-5aliphatic.In certain embodiments, R 2substituted C optionally 1-4aliphatic.In certain embodiments, R 2substituted C optionally 1-3aliphatic.In certain embodiments, R 2substituted C optionally 1-2aliphatic.In certain embodiments, R 2be selected from optionally substituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, neo-pentyl, isopentyl, hexyl, vinyl, propenyl, butenyl, pentenyl and hexenyl.
In certain embodiments, R 2it is substituted benzyl ring optionally.
In certain embodiments, R 2it is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, R 2it is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, R 2it is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, R 2be selected from optionally substituted cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclobutene base, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptenyl, cycloheptadiene base, ring octyl group, cyclooctene base and cyclooctadiene base.
In certain embodiments, R 2it is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 2it is substituted naphthyl ring optionally.
In certain embodiments, R 2to there is 1-2 the ring independently selected from the heterocycle of the saturated or undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there is 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there are 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2it is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 2to there is 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there are 2 rings independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2it is the ring with the heterocycle of the undersaturated monocycle of part of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 2be selected from optionally substituted '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, homopiperazine base, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base, aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyls (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 2to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 2be selected from optionally substituted pyrryl, furyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R 2it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R 2be selected from optionally substituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl and tetrazine base.
In certain embodiments, R 2to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 2the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 2be selected from optionally substituted indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
As described generally hereinbefore, R 1and R 2and insert and form saturated, a undersaturated or aromatic heterocycle partly with 1-3 the heteroatomic 4-8 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-3 the ring independently selected from the saturated heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the saturated heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there are 2 rings independently selected from the saturated heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert together with the atom between them and form a ring with the saturated heterocycle of the 4-8 unit of 1 nitrogen-atoms.In certain embodiments, R 1and R 2and insert and form a kind of following ring that is selected from together with the atom between them: azatropylidene base, azetidinyl, pyrrolidyl, pyrazolidyl, oxazolidinyl, thiazolidyl, piperidyl, piperazinyl and morpholinyl.
In certain embodiments, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Wherein R 5with p be as defined above with described herein.
In certain embodiments, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is replaced by one or more halogens.In the embodiment of some these classes, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000392
In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-3 the ring independently selected from the undersaturated heterocycle of part of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the undersaturated heterocycle of part of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there are 2 rings independently selected from the undersaturated heterocycle of part of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert together with the atom between them and form a ring with the undersaturated heterocycle of part of the 4-8 unit of 1 nitrogen-atoms.In certain embodiments, R 1and R 2and insert and form a kind of following ring that is selected from together with the atom between them: azete base, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, oxazinyl, thiazinyl, azatropylidene base and diazepine base.
In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-3 the ring independently selected from the aromatic heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the aromatic heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert and form one together with the atom between them and there are 2 rings independently selected from the aromatic heterocycle of the heteroatomic 4-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 1and R 2and insert together with the atom between them and form a ring with the aromatic heterocycle of the 4-8 unit of 1 nitrogen-atoms.In certain embodiments, R 1and R 2and insert and form a kind of following ring that is selected from together with the atom between them: pyrryl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
As described generally hereinbefore, by R 1and R 2, and insert the ring quilt-(R that atom between them forms 5) preplace, wherein p is 0-4.As definition hereinbefore, R 5halogen ,-NO 2,-CN ,-N 3,-L-R 6, or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or by R 1and R 2two R on the ring forming 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.
In certain embodiments, R 5it is halogen.In certain embodiments, R 5it is fluorine.In certain embodiments, R 5chlorine.In certain embodiments, R 5it is bromine.In certain embodiments, R 5be-NO 2.In certain embodiments, R 5be-CN.In certain embodiments, R 5be-N 3.In certain embodiments, R 5be-L-R 6.
As definition generally hereinbefore, each R 6be hydrogen independently or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, phenyl, the ring of the saturated or undersaturated carbocyclic ring of part of 3-7 unit, two ring fillings of 8-10 unit, the ring of the carbocyclic ring of undersaturated or aryl partly, there is 1-4 the ring independently selected from the saturated or undersaturated heterocycle of part of the heteroatomic 4-7 unit of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur.
In certain embodiments, R 6hydrogen.In certain embodiments, R 6it is substituted phenyl optionally.In certain embodiments, R 6optionally substituted C of one 1-6aliphatic.In certain embodiments, R 6optionally substituted C of one 1-5aliphatic.In certain embodiments, R 6optionally substituted C of one 1-4aliphatic.In certain embodiments, R 6optionally substituted C of one 1-3aliphatic.In certain embodiments, R 6optionally substituted C of one 1-2aliphatic.
In certain embodiments, R 6it is an optionally ring for the saturated or undersaturated carbocyclic ring of part of substituted 3-7 unit.In certain embodiments, R 6it is an optionally ring for the saturated carbocyclic ring of substituted 3-7 unit.In certain embodiments, R 6it is an optionally ring for the undersaturated carbocyclic ring of part of substituted 3-7 unit.In certain embodiments, R 6be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclohexadienyl and cyclooctadiene base.
In certain embodiments, R 6it is the ring of the carbocyclic rings two ring fillings, the undersaturated or aryl of part of optionally substituted 8-10 unit.In certain embodiments, R 6it is the ring of the carbocyclic ring of two ring fillings of substituted 8-10 unit optionally.In certain embodiments, R 6it is the ring of the undersaturated carbocyclic rings of part of two rings of substituted 8-10 unit optionally.In certain embodiments, R 6it is the ring of the aryl bicyclic carbocyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 6it is naphthyl.
In certain embodiments, R 6to there is 1-4 the ring independently selected from the saturated or undersaturated heterocycle of part of the heteroatomic optionally substituted 4-7 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-4 the ring independently selected from the saturated heterocycle of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-3 the ring independently selected from the saturated heterocycle of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-2 the ring independently selected from the saturated heterocycle of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6it is the ring with the saturated heterocycle of 1 heteroatomic optionally substituted 4-7-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base and homopiperazine base.
In certain embodiments, R 6to there is 1-4 the ring independently selected from the undersaturated heterocycle of part of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6an a kind of 1-3 of having independently selected from the ring of the undersaturated heterocycle of part of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6an a kind of 1-2 of having independently selected from the ring of the undersaturated heterocycle of part of the heteroatomic optionally substituted 4-7-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6it is the ring with the undersaturated heterocycle of part of 1 heteroatomic optionally substituted 4-7-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 6to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 6to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 6-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 6-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 6-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 6-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 6-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, R 6to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 6the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
In certain embodiments, two R on identical nitrogen 6and insert and form saturated, a undersaturated or aromatic heterocycle partly with 1-2 the heteroatomic 4-7 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on identical nitrogen 6and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the heteroatomic saturated heterocycle of nitrogen, oxygen and sulphur.In certain embodiments, two R on identical nitrogen 6and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the undersaturated heterocycle of heteroatomic part of nitrogen, oxygen and sulphur.In certain embodiments, two R on identical nitrogen 6and insert and form one together with the atom between them and there is 1-2 the ring independently selected from the heteroatomic aromatic heterocycle of nitrogen, oxygen and sulphur.In certain embodiments, R 6be selected from two aziridines, azetidin thiazolinyl, oxetene base, thia cyclobutene base, dioxane butenyl, dithia cyclobutene base, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl and pyrimidyl.
As definition generally hereinbefore, n, m and p are selected from an integer of 0,1,2,3 and 4.In certain embodiments, n is 0.In certain embodiments, n is 1.In certain embodiments, n is 2.In certain embodiments, n is 3.In certain embodiments, n is 4.In certain embodiments, m is 0.In certain embodiments, m is 1.In certain embodiments, m is 2.In certain embodiments, m is 3.In certain embodiments, m is 4.In certain embodiments, p is 0.In certain embodiments, p is 1.In certain embodiments, p is 2.In certain embodiments, p is 3.In certain embodiments, p is 4.
As definition generally hereinbefore, q is an integer, is selected from 0,1 and 2.In certain embodiments, q is 0.In certain embodiments, q is 1.In certain embodiments, q is 2.
As definition generally hereinbefore, R 3, R 4, and R 5halogen ,-NO independently of one another 2,-CN ,-N 3,-L-R 6, or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur.
In certain embodiments, R 3it is halogen.In certain embodiments, R 3be-NO 2.In certain embodiments, R 3be-CN.In certain embodiments, R 3be-N 3.
In certain embodiments, R 3substituted C optionally 1-6aliphatic.In certain embodiments, R 3substituted C optionally 1-5aliphatic.In certain embodiments, R 3substituted C optionally 1-4aliphatic.In certain embodiments, R 3substituted C optionally 1-3aliphatic.In certain embodiments, R 3substituted C optionally 1-2aliphatic.In certain embodiments, R 3be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, neo-pentyl, isopentyl and hexyl.
In certain embodiments, R 3be-L-R 6.
In certain embodiments, R 3it is substituted phenyl optionally.
In certain embodiments, R 3it is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, R 3it is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, R 3be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
In certain embodiments, R 3it is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, R 3be selected from cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclopentadienyl, cyclohexadienyl, cycloheptadiene base and cyclooctadiene base.
In certain embodiments, R 3it is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 3it is naphthyl.
In certain embodiments, R 3to there is 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there are 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3it is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 3be selected from '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, dioxane amyl group, dithia cyclopentyl, oxa-cyclopentyl, thia cyclopentyl, piperidyl, piperazinyl, morpholinyl, oxa-cyclohexyl, thia cyclohexyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base and homopiperazine base.
In certain embodiments, R 3to there is 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3be selected from aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 3to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 3be selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R 3it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R 3be selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, R 3to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 3the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 3be selected from indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
In certain embodiments, R 4it is halogen.In certain embodiments, R 4be-NO 2.In certain embodiments, R 4be-CN.In certain embodiments, R 4be-N 3.
In certain embodiments, R 4substituted C optionally 1-6aliphatic.In certain embodiments, R 4substituted C optionally 1-5aliphatic.In certain embodiments, R 4substituted C optionally 1-4aliphatic.In certain embodiments, R 4substituted C optionally 1-3aliphatic.In certain embodiments, R 4substituted C optionally 1-2aliphatic.In certain embodiments, R 4be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, neo-pentyl, isopentyl and hexyl.
In certain embodiments, R 4be-L-R 6.
In certain embodiments, R 4it is substituted phenyl optionally.
In certain embodiments, R 4it is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, R 4it is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, R 4be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
In certain embodiments, R 4it is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, R 4be selected from cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclopentadienyl, cyclohexadienyl, cycloheptadiene base and cyclooctadiene base.
In certain embodiments, R 4it is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 4it is naphthyl.
In certain embodiments, R 4to there is 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there are 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4it is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 4be selected from '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, dioxane amyl group, dithia cyclopentyl, oxa-cyclopentyl, thia cyclopentyl, piperidyl, piperazinyl, morpholinyl, oxa-cyclohexyl, thia cyclohexyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base and homopiperazine base.
In certain embodiments, R 4to there is 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4be selected from aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 4to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 4be selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R 4it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R 4be selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, R 4to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 4the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 4be selected from indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
In certain embodiments, R 5it is halogen.In certain embodiments, R 5be-NO 2.In certain embodiments, R 5be-CN.In certain embodiments, R 5be-N 3.
In certain embodiments, R 5substituted C optionally 1-6aliphatic.In certain embodiments, R 5substituted C optionally 1-5aliphatic.In certain embodiments, R 5substituted C optionally 1-4aliphatic.In certain embodiments, R 5substituted C optionally 1-3aliphatic.In certain embodiments, R 5substituted C optionally 1-2aliphatic.In certain embodiments, R 5be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, neo-pentyl, isopentyl and hexyl.
In certain embodiments, R 5be-L-R 6.
In certain embodiments, R 5it is substituted phenyl optionally.
In certain embodiments, R 5it is the ring of the carbocyclic ring of the saturated or undersaturated monocycle of part of optionally substituted 3-8 unit.In certain embodiments, R 5it is the ring of the carbocyclic ring of the saturated monocycle of substituted 3-8 unit optionally.In certain embodiments, R 5be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
In certain embodiments, R 5it is the ring of the carbocyclic ring of the undersaturated monocycle of part of substituted 3-8 unit optionally.In certain embodiments, R 5be selected from cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclopentadienyl, cyclohexadienyl, cycloheptadiene base and cyclooctadiene base.
In certain embodiments, R 5it is the aryl bicyclic ring of substituted 8-10 unit optionally.In certain embodiments, R 5it is naphthyl.
In certain embodiments, R 5to there is 1-2 the ring independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there are 2 rings independently selected from the heterocycle of the saturated monocycle of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5it is the ring with the heterocycle of the saturated monocycle of 1 heteroatomic optionally substituted 3-8 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 5be selected from '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, dioxane amyl group, dithia cyclopentyl, oxa-cyclopentyl, thia cyclopentyl, piperidyl, piperazinyl, morpholinyl, oxa-cyclohexyl, thia cyclohexyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base and homopiperazine base.
In certain embodiments, R 5to there is 1-2 the ring independently selected from the heterocycle of the undersaturated monocycle of part of the heteroatomic optionally substituted 3-8 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5be selected from aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyl (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl and thiazolinyl.
In certain embodiments, R 5to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-6 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there is 1-3 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there is 1-2 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there are 2 hetero-aromatic rings independently selected from the monocycle of the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of 1 heteroatomic optionally substituted 5-unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 5be selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-4 nitrogen-atoms.In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-3 nitrogen-atoms.In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1-2 nitrogen-atoms.In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 2 nitrogen-atoms.In certain embodiments, R 5it is the hetero-aromatic ring with the monocycle of the optionally substituted 6-unit of 1 nitrogen-atoms.In certain embodiments, R 5be selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, R 5to there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there are 1-3 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5to there are 1-2 the hetero-aromatic rings independently selected from two rings of the heteroatomic optionally substituted 8-10 unit of nitrogen, oxygen and sulphur.In certain embodiments, R 5the hetero-aromatic rings with two rings of the 1 heteroatomic optionally substituted 8-10 unit that is selected from nitrogen, oxygen and sulphur.In certain embodiments, R 5be selected from indyl, indazolyl, benzofuryl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzotriazole base, azaindolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl and cinnolines base.
In certain embodiments, two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 1-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 3group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 1 heteroatomic 4-8 unit condensing that is selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 2-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 3group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 2 heteroatomic 4-8 units that condense independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 3group and insert together with the atom between them and form a benzyl ring.In certain embodiments, two R on ring B 3group and insert and form one together with the atom between them and be selected from following ring: '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base, homopiperazine base, aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyls (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, two R on ring A 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 1-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 4group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 1 heteroatomic 4-8 unit condensing that is selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 2-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 4group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 2 heteroatomic 4-8 units that condense independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 4group and insert together with the atom between them and form a benzyl ring.In certain embodiments, two R on ring B 4group and insert and form one together with the atom between them and be selected from following ring: '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base, homopiperazine base, aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyls (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
In certain embodiments, by R 1and R 2two R on the ring forming 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 1-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 5group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 1 heteroatomic 4-8 unit condensing that is selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 2-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them.In certain embodiments, two R on ring B 5group and inserting forms a kind of saturated, ring of undersaturated or aryl partly with 2 heteroatomic 4-8 units that condense independently selected from nitrogen, oxygen and sulphur together with the atom between them.In some embodiment of formula I, two R on ring B 5group and insert together with the atom between them and form a benzyl ring.In certain embodiments, two R on ring B 5group and insert and form one together with the atom between them and be selected from following ring: '-aziridino (aziridinyl), Oxyranyle, thiirane base, oxa-'-aziridino (oxaziridinyl), diepoxide for example base, azetidinyl, oxetanyl, Thietane base, diazetidine base, dioxetanes alkyl, dithietane base, pyrrolidyl, oxa-cyclopentyl, thia cyclopentyl, imidazolidyl, pyrazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, dioxane amyl group, dithia cyclopentyl, piperidyl, oxa-cyclohexyl, thia cyclohexyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxacyclohexyl, dithia cyclohexyl, azepan base, oxepane alkyl, thia suberane base, homopiperazine base, aziridinyl (azirinyl), oxirine base (oxirenyl), thia cyclopropenyl radical (thiirenyl), two aziridinyls (diazirinyl), azete base (azetyl), oxetene base (oxetyl), thia cyclobutene base (thietyl), dioxane butenyl (dioxetyl), dithia cyclobutene base (dithietyl), imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
As definition generally hereinbefore, L is covalent linkage or the C of substituted divalence optionally 1- 6hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is covalent linkage.In certain embodiments, L is the C of substituted divalence optionally 1-6hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is the C of substituted divalence optionally 1-5hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is the C of substituted divalence optionally 1-4hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is the C of substituted divalence optionally 1-3hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is the C of substituted divalence optionally 1-2hydrocarbon chain, wherein, one or two methylene unit of L optionally and independently by-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute.In certain embodiments, L is-Cy-.In certain embodiments, L is-O-.In certain embodiments, L is-S-.In certain embodiments, L is-N (R 6)-.In certain embodiments, L be-C (O)-.In certain embodiments, L be-C (S)-.In certain embodiments, L is-C (O) N (R 6)-.In certain embodiments, L is-N (R 6) C (O) N (R 6)-.In certain embodiments, L is-N (R 6) C (O)-.In certain embodiments, L is-N (R 6) C (O) O-.In certain embodiments, L is-OC (O) N (R 6)-.In certain embodiments, L be-S (O)-.In certain embodiments, L is-S (O) 2-.In certain embodiments, L is-S (O) 2n (R 6)-.In certain embodiments, L is-N (R 6) S (O) 2-.In certain embodiments, L be-OC (O)-.In certain embodiments, L is-C (O) O-.
In certain embodiments, L is-CH 2-Cy-.In certain embodiments, L is-CH 2-O-.In certain embodiments, L is-CH 2-S-.In certain embodiments, L is-CH 2-N (R 6)-.In certain embodiments, L is-CH 2-C (O)-.In certain embodiments, L is-CH 2-C (S)-.In certain embodiments, L is-CH 2-C (O) N (R 6)-.In certain embodiments, L is-CH 2-N (R 6) C (O) N (R 6)-.In certain embodiments, L is-CH 2-N (R 6) C (O)-.In certain embodiments, L is-CH 2-N (R 6) C (O) O-.In certain embodiments, L is-CH 2-OC (O) N (R 6)-.In certain embodiments, L is-CH 2-S (O)-.In certain embodiments, L is-CH 2-S (O) 2-.In certain embodiments, L is-CH 2-S (O) 2n (R 6)-.In certain embodiments, L is-CH 2-N (R 6) S (O) 2-.In certain embodiments, L is-CH 2-OC (O)-.In certain embodiments, L is-CH 2-C (O) O-.
In certain embodiments, L is-Cy-CH 2-.In certain embodiments, L is-O-CH 2-.In certain embodiments, L is-S-CH 2-.In certain embodiments, L is-N (R 6)-CH 2-.In certain embodiments, L is-C (O)-CH 2-.In certain embodiments, L is-C (S)-CH 2-.In certain embodiments, L is-C (O) N (R 6)-CH 2-.In certain embodiments, L is-N (R 6) C (O) N (R 6)-CH 2-.In certain embodiments, L is-N (R 6) C (O)-CH 2-.In certain embodiments, L is-N (R 6) C (O) O-CH 2-.In certain embodiments, L is-OC (O) N (R 6)-CH 2-.In certain embodiments, L is-S (O)-CH 2-.In certain embodiments, L is-S (O) 2-CH 2-.In certain embodiments, L is-S (O) 2n (R 6)-CH 2-.In certain embodiments, L is-N (R 6) S (O) 2-CH 2-.In certain embodiments, L is-OC (O)-CH 2-.In certain embodiments, L is-C (O) O-CH 2-.
As definition generally hereinbefore,-Cy-is an optionally substituted divalence ring, this ring is selected from a 3-7 unit, the undersaturated ring alkenylene of saturated or part ring, one has 1-4 independently selected from nitrogen, the heteroatomic 4-7 unit of oxygen and sulphur, the undersaturated heterocycle alkylene of saturated or part basic ring, phenylene, one has 1-4 independently selected from nitrogen, the heteroarylidene of the monocycle of the heteroatomic 5-6 unit of oxygen and sulphur, the arylidene of two rings of a 8-10 unit, or one have 1-4 independently selected from nitrogen, the heteroarylidenes of two rings of the heteroatomic 8-10 unit of oxygen and sulphur.
In certain embodiments, the invention provides a kind of compound with formula I-a or I-b:
Figure BDA0000484103910000591
Figure BDA0000484103910000601
Or its a kind of pharmacy acceptable salt, wherein encircle A, ring B, X, Y, R 1, R 2, R 3, R 4, m, n and p respectively naturally as defined above and described here.
In some embodiment of formula I-a and I-b, q is 0.Therefore, in certain embodiments, the invention provides a kind of compound with formula II-a or II-b:
Figure BDA0000484103910000602
Or its a kind of pharmacy acceptable salt, wherein encircle A, ring B, X, Y, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula II-a and II-b, Y is a covalent linkage.Therefore, in certain embodiments, the invention provides a kind of compound with formula III-a or III-b:
Figure BDA0000484103910000603
Figure BDA0000484103910000611
Or its a kind of pharmacy acceptable salt, wherein encircle A, ring B, X, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula III-a and III-b, X is O.Therefore, in certain embodiments, the invention provides a kind of compound with formula IV-a or IV-b:
Figure BDA0000484103910000612
Or its a kind of pharmacy acceptable salt, wherein encircle A, ring B, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula IV-a and IV-b, ring A has 1-4 the hetero-aromatic ring independently selected from the monocycle of heteroatomic 5 yuan of nitrogen, oxygen and sulphur.In some embodiment of formula IV-a and IV-b, ring A has 1-3 the hetero-aromatic ring independently selected from the monocycle of heteroatomic 5 yuan of nitrogen, oxygen and sulphur.In some embodiment of formula IV-a and IV-b, ring A has 1-2 the hetero-aromatic ring independently selected from the monocycle of heteroatomic 5 yuan of nitrogen, oxygen and sulphur.In some embodiment of formula IV-a and IV-b, ring A has 2 hetero-aromatic rings independently selected from the monocycle of heteroatomic 5 yuan of nitrogen, oxygen and sulphur.In some embodiment of formula IV-a and IV-b, ring A has 1 hetero-aromatic ring that is selected from the monocycle of heteroatomic 5 yuan of nitrogen, oxygen and sulphur.In some embodiment of formula IV-a and IV-b, ring A is selected from optionally substituted pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, triazolyl and tetrazyl.
In some embodiment of formula IV-a and IV-b, ring A is triazolyl.Therefore, in certain embodiments, the invention provides the compound with formula V-a, V-b, V-c and V-d:
Figure BDA0000484103910000621
Or its a kind of pharmacy acceptable salt, wherein encircle B, R 1, R 2, R 3, R 4with and n respectively naturally as defined above and described here, and m is 0 or 1.
In some embodiment of formula IV-a and IV-b, ring A is imidazolyl.Therefore, in certain embodiments, the invention provides the compound with formula V-e, V-f, V-g, V-h, V-i and V-j:
Figure BDA0000484103910000631
Or its a kind of pharmacy acceptable salt, wherein encircle B, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula IV-a and IV-b, ring A is pyrazolyl.Therefore, in certain embodiments, the invention provides the compound with formula V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s and V-t:
Figure BDA0000484103910000641
Or its a kind of pharmacy acceptable salt, wherein encircle B, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula IV-a and IV-b, ring A is pyrryl.Therefore, in certain embodiments, the invention provides the compound with formula V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc and V-dd:
Figure BDA0000484103910000652
Figure BDA0000484103910000661
Figure BDA0000484103910000671
Or its a kind of pharmacy acceptable salt, wherein encircle B, R 1, R 2, R 3, R 4, m and n respectively naturally as defined above and described here.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is substituted phenyl optionally.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more optionally substituted methyl substituted phenyl.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by a substituted methyl substituted phenyl optionally.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two substituted methyl substituted phenyl optionally.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by least one halogen.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by least two halogens.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, and this methyl is replaced by three halogens.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more-CF 3the phenyl that group replaces.In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two-CF 3the phenyl that group replaces.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is:
Figure BDA0000484103910000681
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, R 1and R 2and insert form together with the atom between them a kind of 1-3 of having heteroatomic 4-8 unit independently selected from nitrogen, oxygen and sulphur saturated, the ring of undersaturated or aromatic heterocycle partly, the ring quilt-(R wherein forming thus 5) preplace.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000691
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is replaced by one or more halogen.In some such embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000692
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is substituted phenyl and by R optionally 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000693
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more optionally substituted methyl substituted phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two substituted methyl substituted phenyl and by R optionally 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000702
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, this methyl is replaced by least one halogen, and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000703
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, this methyl is replaced by three halogens, and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000711
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more-CF 3group replace phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000712
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two-CF 3group replace phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000713
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is:
Figure BDA0000484103910000714
and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000715
wherein R 5with p be as defined above with described herein.
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is substituted phenyl and by R optionally 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000721
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more optionally substituted methyl substituted phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000722
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two substituted methyl substituted phenyl and by R optionally 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000723
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, this methyl is replaced by least one halogen, and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more methyl substituted phenyl, this methyl is replaced by three halogens, and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000732
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by one or more-CF 3group replace phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is by two-CF 3group replace phenyl and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000734
In some embodiment of formula V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, V-l, V-m, V-n, V-o, V-p, V-q, V-r, V-s, V-t, V-u, V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc or V-dd, ring B is:
Figure BDA0000484103910000741
and by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is:
Figure BDA0000484103910000742
One embodiment of the present of invention are a kind of compounds with formula I, or its a kind of pharmacy acceptable salt, wherein:
Ring A is selected from optionally substituted ring of following one: phenyl, 8-10-unit aryl bicyclic ring, has independently selected from 1-4 heteroatomic 5-6-unit's monocycle hetero-aromatic ring of nitrogen, oxygen and sulphur and has the heteroatomic 8-10-of independently selected from nitrogen, oxygen and sulphur 1-4 unit two ring hetero-aromatic rings;
Ring B is an optionally substituted ring, this ring is selected from the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur;
X is selected from O, S, N-CN and NR;
R is hydrogen or is a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, have independently selected from the 1-2 of nitrogen, oxygen and sulphur heteroatomic 3-8 unit saturated or the ring of undersaturated heterocycle partly, phenyl, and there is the heteroatomic 5-6 of independently selected from nitrogen, oxygen and sulphur 1-4 unit hetero-aromatic ring;
Y is covalent linkage or the C of substituted divalence optionally 1-4alkyl, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute;
R 1and R 2be hydrogen independently of one another or be selected from following optionally substituted group: C 1-6aliphatic, ring 3-8 unit, saturated or the undersaturated monocycle carbocyclic ring of part, phenyl, two cyclophane rings of 8-10 unit, there is the ring of 1-2 or part undersaturated monocyclic heterocycles unit, saturated independently selected from the heteroatomic 3-8 of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
R 1and R 2and insert form together with the atom between them a kind of have the heteroatomic 4-8 of independently selected from nitrogen, oxygen and sulphur 1-3 unit saturated, the ring of undersaturated or aromatic heterocycle partly, the ring quilt-(R wherein forming thus 5) preplace;
N, m and p are selected from an integer of 0,1,2,3 and 4;
Q is an integer, is selected from 0,1 and 2;
R 3, R 4, and R 5halogen ,-NO independently of one another 2,-CN ,-N 3,-L-R 6, or be selected from following optionally substituted group: C 1-6aliphatic group, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is 1-2 the ring independently selected from the saturated or undersaturated monocyclic heterocycles of part of the heteroatomic 3-8 unit of nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
Two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
Two R on ring A 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
By R 1and R 2two R on the ring forming 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them;
L is covalent linkage or the C of substituted divalence optionally 1-6alkyl, wherein, one or two methylene unit of L is optionally and independently by following substituting-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-;
-Cy-is an optionally substituted divalence ring, this ring is selected from a 3-7 unit, the saturated or undersaturated ring alkenylene of part ring, one have 1-4 independently selected from the heteroatomic 4-7 of nitrogen, oxygen and sulphur unit, the saturated or undersaturated heterocycle alkylene of part basic ring, phenylene, one has 1-4 the heteroarylidene independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, the arylidene of two rings of a 8-10 unit, and one have 1-4 the heteroarylidenes independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; And
Each R 6be hydrogen independently or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, ring 3-7 unit, saturated or the undersaturated carbocyclic ring of part, two ring fillings of 8-10 unit, the ring of the carbocyclic ring of undersaturated or aryl partly, there is the ring of 1-4 or part undersaturated heterocycle unit, saturated independently selected from the heteroatomic 4-7 of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; Or:
Two R on identical nitrogen 6and insert and form saturated, a undersaturated or aromatic heterocycle partly with 1-2 the heteroatomic 4-7 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them.
In a specific embodiment of compound with formula I, this compound is not a kind of compound of listing in table 1A.
Table 1A.
Figure BDA0000484103910000771
Figure BDA0000484103910000781
In a kind of another specific embodiment of compound with formula I, this compound is not a kind of compound of listing in table 1B.
Table 1B.
Figure BDA0000484103910000801
Figure BDA0000484103910000811
In a kind of another specific embodiment of compound with formula I, this compound is not a kind of compound of listing in table 1C.
Table 1C.
Figure BDA0000484103910000812
Figure BDA0000484103910000821
Exemplary compound of the present invention is listed in table 2.
Table 2. exemplary compound of the present invention
Figure BDA0000484103910000841
Figure BDA0000484103910000861
Figure BDA0000484103910000871
Figure BDA0000484103910000881
Figure BDA0000484103910000891
Figure BDA0000484103910000901
Figure BDA0000484103910000911
Figure BDA0000484103910000921
Figure BDA0000484103910000931
An alternative embodiment of the invention is a kind of compound by structural formula (VI) representative:
Or its a kind of pharmacy acceptable salt, wherein:
Z is selected from N, CH and C (Cl);
R 1hydrogen; And
R 2be selected from-CH 2-oxazoles-5-base ,-CH 2-pyrimidine-5-base ,-CH 2-(1-methylpyrrolidin-3-yl) or or:
R 1and R 2form with together with the nitrogen-atoms of their combinations
Figure BDA0000484103910000942
Figure BDA0000484103910000943
4-hydroxy piperidine-1-base, pyrrolidin-1-yl or azetidin-1-base, wherein optionally and independently replaced by 2 substituting groups of as many as on this pyrrolidin-1-yl and the each comfortable 3-of azetidin-1-base position, and this substituting group is selected from fluorine ,-CF 3,-CH 3,-OH, pyridine-2-base ,-CH 2-N (CH 3) 2,-CH 2-NH-CH 3,-CH 2-NH 2,-CN ,-C (O)-O-CH 3; And
R 7be selected from fluorine ,-OH and-CF 3.
The representational compound with structural formula VI comprises:
Figure BDA0000484103910000951
Figure BDA0000484103910000961
Figure BDA0000484103910000971
An alternative embodiment of the invention is a kind of compound by any representative in following structural formula, or its a kind of pharmacy acceptable salt:
Figure BDA0000484103910000992
Figure BDA0000484103910001001
Preparation and administration
An alternative embodiment of the invention is a kind of composition, and said composition comprises a kind of compound of the present invention, or its a kind of pharmacy acceptable salt, and a kind of pharmaceutically acceptable carrier, adjuvant or vehicle.The value of the compound in a kind of composition of the present invention is a value that can suppress CRM1 in biological material or patient with measuring.In certain embodiments, composition of the present invention is formulated for and delivers medicine to the patient who needs said composition.In certain embodiments, a kind of composition of the present invention be formulated for that oral, intravenous administration, subcutaneous administration, intraperitoneal are used or dermal administration in it being had on the patient who needs.
As used herein, term " patient " refers to a kind of animal.In certain embodiments, this animal is a kind of Mammals.In certain embodiments, this patient is a kind of patient for animals (, a kind of inhuman mammalian subject).In certain embodiments, this patient is dog.In other embodiment, this patient is the mankind.
" pharmaceutically or acceptable on pharmacology " comprises in the time giving as suitable a kind of animal, a people, do not produce molecular entities disadvantageous, irritated or other untoward reactions and composition.For the mankind's administration, preparation should meet the sterility, pyrogenicity that require as FDA biotechnological formulation standard office chamber (Office of Biologics standards) and the standard of security and purity generally.
Phrase " pharmaceutically acceptable carrier, auxiliary or vehicle " refers to a kind of nontoxic carrier, adjuvant or the vehicle that can not destroy with the pharmacological activity of the compound being formulated together with it, and when being nontoxic when the dosage of this compound of delivery treatments amount gives effectively.The pharmaceutically acceptable carrier that can use in composition of the present invention, adjuvant or vehicle are including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein (as human serum albumin), buffer substance (as phosphoric acid salt), glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen are (as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt), colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, based on cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene block polymer, polyoxyethylene glycol and lanolin.
Composition of the present invention can oral administration, parenteral (comprising subcutaneous, intramuscular, intravenously and intradermal) administration, by sucking spray delivery, topical, rectal administration, intranasal administration, buccal administration, vagina administration or via the administration of embedded type reservoir.In certain embodiments, the compound providing or composition be can intravenous administration and/or to intraperitoneal administration.
As used herein term " parenteral " comprise in subcutaneous, intracutaneous, intravenous, muscle, intraocular, intravitreous, IA, endarterial, intrasynovial, intrasternal, film, intralesional, liver, injection intraperitoneal intralesional and encephalic or implantttion technique.Preferably, by said composition oral administration, subcutaneous administration, intraperitoneal administration or intravenously administrable.
Pharmaceutically acceptable composition of the present invention can be peroral administration with the acceptable formulation of any per os, and this formulation is including, but not limited to capsule, tablet, aqueous suspension, dispersion agent and solution.In the situation of the tablet for orally using, conventional carrier comprises lactose and W-Gum.Typically also add lubricant, as Magnesium Stearate.For with capsule form oral administration, useful thinner comprises lactose and dried corn starch.In the time that needs orally use aqueous suspension and/or emulsion, this activeconstituents can suspend or be dissolved in a kind of oil phase and with emulsification and/or suspension agent combination.If desired, can also add some sweetner, spices or tinting material.
In certain embodiments, a kind of oral preparation be formulated for immediately discharge or continue/release that postpones.
Comprise capsule, tablet, pill, pulvis and granule for peroral administration solid dosage.In this type of solid dosage, active compound mixes with following material: at least one inertia, pharmaceutically acceptable vehicle or carrier, as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or a) weighting agent or extender as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as Cellulose,ether with glycolic acid, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar-agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate, and sodium carbonate, e) solution retarding agent is as paraffin, f) absorption enhancer is as quaternary ammonium salt, g) wetting agent is as ethanoyl alcohol and Zerol, h) absorption agent as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP, and composition thereof.In the case of capsule, tablet and pill, this formulation can also comprise buffer reagent.
The composition that is applicable to buccal or sublingual administration comprises tablet, lozenge and pastille, wherein this activeconstituents is prepared as sugared with a kind of carrier together with gum arabic, tragacanth gum or gelatin and glycerine.
Use vehicle as lactose (lactose) or toffee (milk sugar), and high molecular weight polyethylene glycol etc., the solids composition of similar type can also be used as the weighting agent in soft and hard-filled gelatin capsule.The solid dosage of tablet, dragee, capsule, pill and granule can be used dressing and involucrum, as enteric coating and other in the known dressing preparation of medicine formulation art.They can optionally comprise opalizer and can be a kind of compositions, and said composition is in certain part of this enteron aisle, optionally, with a kind of delay mode, only or preferentially discharge one or more activeconstituentss.The example of operable embedding composition comprises polymkeric substance and wax class.
A kind of compound of the present invention can also be the microencapsulation form in having one or more vehicle as already pointed out.In this type of solid dosage, compound of the present invention and at least one inert diluent can be mixed as sucrose, newborn sugar and starch.As general custom, this type of formulation can also comprise the other material except inert diluent, and for example, compressing tablet lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.
Can pass through, for example, a kind of outer coatings of the preparation on tablet or capsule will be used for peroral administration composition and be designed to, in the time of its process digestive tube, protect this activeconstituents not degraded.
In another embodiment, can provide a kind of compound of the present invention with the form of (or " delay " or " continuing ") release composition of a kind of prolongation.The composition of this delayed release comprises the of the present invention a kind of compound with a kind of delayed release combination of components.Composition allows the targeting compounds providing to be discharged into a gi tract bottom like this, for example, be discharged into small intestine, large intestine, colon and/or rectum.In certain embodiments, that the delayed release compositions that comprises a kind of compound of the present invention further comprises a kind of enteric or pH dependency dressing, as Cellacefate, and other phthalic ester (for example, poly-acetic acid O-phthalic vinyl acetate, methacrylic ester (acrylic resin)).Alternately, by the polymkeric substance that pH susceptibility methacrylic ester dressing, pH sensitive polymer microballoon is provided or degrades via hydrolysis, the composition of this delayed release provides to the control of small intestine and/or colon and discharges.The composition of this delayed release can be prepared together with auxiliary material hydrophobic or gel or dressing.Can be further by the dressing that digested by bacterial enzyme as amylose starch or pectin, by pH dependent polymers, by swelling in time hydrogel suppository (pulsincap (Pulsincap)), by the hydrogel dressing of time dependent and/or by being connected to the vinylformic acid dressing on azo aromatic series key, thereby provide sending of colon.
In certain embodiments, the composition of delayed release of the present invention comprises hypromellose, Microcrystalline Cellulose and a kind of lubricant.The mixture preparation of a kind of compound of the present invention, hypromellose and Microcrystalline Cellulose can be entered for peroral administration tablet or capsule.In certain embodiments, this mixture is carried out granular and is pressed into tablet.
Alternately, for rectal administration, pharmaceutically acceptable composition of the present invention can carry out administration with the form of suppository.These can be by by a kind of suitable non-irritating vehicle and compound of the present invention preparation, thus this vehicle be at room temperature solid and under rectal temperature, be liquid and therefore in rectum, will dissolve release medicine.This type of material comprises oleum theobromatis, beeswax and polyoxyethylene glycol.
Can also be by pharmaceutically acceptable composition of the present invention administration partly, especially, in the time that treatment target spot comprises topical application and is easy to approaching region or organ, comprise the disease of eye, skin or low level enteron aisle.Each suitable local preparation for these regions or organ is easy to preparation.
Topical application for low level enteron aisle can complete with rectal suppository preparation (seeing above) or suitable enema preparation.Can also use topical transdermal patch.
For other topical applications, pharmaceutically acceptable composition of the present invention can be formulated in a kind of suitable ointment, and this ointment packets is containing suspending or being dissolved in the active ingredient in one or more carriers.For the carrier of the topical of compound of the present invention including, but not limited to, mineral oil, paraffin oil, Chinese wax cream, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers.Alternately, pharmaceutically acceptable composition of the present invention can be formulated in a kind of suitable washing lotion or emulsifiable paste, and this washing lotion or emulsifiable paste comprise suspension or be dissolved in the active ingredient in one or more pharmaceutically acceptable carriers.Alternately, can prepare this medicinal compositions with a kind of suitable washing lotion or emulsifiable paste, this washing lotion or emulsifiable paste comprise suspension or are dissolved in the active ingredient in a kind of carrier with suitable emulsifying agent.In certain embodiments, suitable carrier including, but not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.In other embodiments, suitable carrier including, but not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water and penetration enhancers.
Use for ophthalmology, pharmaceutically acceptable composition of the present invention can be formulated as at the micronization suspension waiting in Sterile Saline that ooze, pH regulator, or preferably, be formulated as at the solution (being with or without such as benzalkonium chloride of sanitas) waiting in Sterile Saline that ooze, pH regulator.Alternately, use for ophthalmology, this pharmaceutically acceptable composition can be formulated in to a kind of ointment as in Vaseline.
Pharmaceutically acceptable composition of the present invention can also be carried out to administration by nose with aerosol or inhalation.Such composition is according to the preparation of technology known in pharmaceutical formulation field and can uses phenylcarbinol or such composition is prepared as the solution in salt solution by other suitable sanitass, absorption enhancer, fluorocarbon and/or other the conventional solubilisings or the dispersion agent that strengthen bioavailability.
In certain embodiments, pharmaceutically acceptable composition of the present invention is configured to for oral administration.
In certain embodiments, pharmaceutically acceptable composition of the present invention is configured to for intraperitoneal administration.
In certain embodiments, pharmaceutically acceptable composition of the present invention is configured to for topical.
Can combine with these solid support materials so as to produce a kind of composition in a single formulation compound of the present invention amount by depend on the main body that is treated, the concrete mode that gives and employing compound activity and change.Preferably, composition should be mixed with like this so that between 0.01 to 100mg/kg body weight/day the dosage of inhibitor can be delivered medicine to the patient who accepts said composition.
It is to be further understood that, to depend on many factors for any specific patient's concrete dosage and treatment plan, comprise activity, age, body weight, general health, sex, diet, administration time, excretion rate, drug regimen, treatment doctor's judgement and the seriousness of the specified disease that will treat of the particular compound of use.The amount of the compound of the present invention in said composition is also by the specific compound depending in said composition.
Can be used in other the pharmaceutically acceptable carriers in medicinal compositions of the present invention, adjuvant or vehicle are including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, self-emulsifying drug delivery systems (SEDDS) is as d--tocopherol polyethyleneglycol 1000 succinates, the tensio-active agent using in pharmaceutical dosage form is as tween or other similar polymkeric substance delivery matrices, serum protein is as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen, (as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt), colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, based on cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene block polymer, polyoxyethylene glycol and lanolin.Cyclodextrin as α-, β-and γ-cyclodextrin, or the derivative of chemically modified (for example hydroxyalkyl cyclodextrin), comprises 2-and 3-hydroxypropyl-beta-cyclodextrin, or other solubilising derivatives also can be advantageously used in and strengthen sending of compound described herein.
Medicinal compositions of the present invention preferably carries out administration by oral administration or by injection.Medicinal compositions of the present invention can comprise any conventional nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle.In some cases, the pH of this preparation can regulate with pharmaceutically acceptable acid, alkali or buffer reagent, thereby strengthens the compound of this preparation or the stability of its delivery form.
This medicinal compositions can be the form in aseptic injection, for example, is a kind of aseptic injection water-based or oily suspensions.This suspension can be according to technology as known in the art, uses suitable dispersion or wetting agent (for example, as,, tween 80) and suspension agent to prepare.The goods of this aseptic injection can also be a kind of in nontoxic, the acceptable thinner of parenteral or solvent aseptic injectable solution or the suspension of (for example, in 1,3 butylene glycol solution).The acceptable vehicle that wherein can adopt and solvent are N.F,USP MANNITOL, water, Ringer's solution (Ringer ' s solution) and isotonic sodium chlorrde solution.In addition, in aseptic fixing oily convention, be used as solvent or suspension medium.For this purpose, the fixed oil of any gentleness be can adopt, synthetic monoglyceride or triglyceride comprised.Lipid acid, if the glyceride derivative of oleic acid and it is useful in the preparation of injection, because they are natural pharmaceutically acceptable oil, as sweet oil or Viscotrol C, the especially form of the polyoxyethylene in them.These oil solutions or suspension can also comprise long-chain alcohol thinner or dispersion agent, or conventional dispersion agent in carboxymethyl cellulose or the similar pharmaceutically preparation of acceptable formulation (as emulsion and/or suspension).Also can use other conventional tensio-active agent for preparing object, as tween (Tweens) or this dish (Spans) and/or other similar emulsifying agents or bioavailability toughener, they are pharmaceutically commonly used in acceptable solid, liquid or other formulation manufacture.
When composition of the present invention comprises while having the compound of formula described here and the combination of one or more other therapeutical agents or preventive, this compound and this other agent all should be in monotherapy scheme bio-occlusion pharmaceutical quantities about 1% to 100% between dosage level, and the more preferably dosage level between about 5% to 95%.This or these additives can with these compounds of the present invention administration individually, as the administration partially of multiple doses scheme.Alternately, this or these additives can be a kind of parts of single dosage form, can be in a kind of single composition together with compound of the present invention.
Compound described here is passable, for example, by in injection, intravenously, intra-arterial, intraocular, vitreum, subcutaneous (subdermallym) or per os, buccal, intranasal, wear mucous membrane ground, local, with ophthalmic preparation or by inhalation administration, the dosage range using is, every 4 to 120 hours, from about body weight of 0.5 to about 100mg/kg, or alternately with from about 1mg to the about dosage of the scope of 1000mg/ agent, or require to determine according to specific medicine.Consider to give of the present invention a kind of compound or its a kind of composition of a significant quantity in this method, to reach effect desirable or explanation.Typically, medicinal compositions of the present invention will from every day about 1 time to about 6 administrations, or alternately, as a kind of continuous infusion administration.This type of administration can be used as chronic or acute therapy.Thereby the amount that can produce a kind of activeconstituents of single formulation with the combination of a kind of solid support material will depend on the main body for the treatment of and specific administering mode and change.A kind of typical preparation is by the active compound (w/w) that comprises from about 5% to about 95%.Alternately, a kind of preparation can comprise from about 20% to about 80% active compound.
Can lower than or higher than those dosage of above enumerating.Concrete dose and treatment plan for any specific patient will depend on many factors, comprise the activity of the compound of concrete use, age, body weight, general health, sex, diet, administration time, excretion rate, the seriousness of drug regimen and disease, illness or symptom and inducement, the disposal of patient to this disease, illness or symptom and treatment doctor's judgement.
According to the improvement of patient's illness, if necessary, can administration compound of the present invention, the maintenance dose of composition or combination.Subsequently, in the time that symptom has been alleviated to desirable level, can be reduced to using the dosage of administration or frequency or both as the function of these symptoms such level that the illness of improvement is kept.But patient can require the long-term intermittent treatment based on any disease symptoms recurrence.
The use of compound and pharmaceutically acceptable composition
Common compound described here and composition are useful to suppressing CRM1, and are therefore useful for one or more disorders relevant to the activity of CRM1 for the treatment of.Therefore, in certain embodiments, the invention provides the disorderly method of a kind of CRM1-of being used for the treatment of mediation, the method comprises a kind of compound of the present invention or its pharmacy acceptable salt or composition is delivered medicine to and need this step of its patient.Compound described here and composition can also be delivered medicine at the cell of cultivating in system, for example in vivo or in vitro, or deliver medicine to an experimenter, for example, in vivo, thereby treatment, prevent and/or diagnose multiple disorder, comprising below those described here.
Can be in vivo, external or in clone, measure the activity of the compound of the inhibitor as CRM1 using in the present invention.List in illustration for the detailed conditions of measuring the compound as CRM1 inhibitor using in the present invention.
As used in this, term " treatment " (" treat " or " treatment ") be defined as individually or with a kind of the second compound combination by a kind of compound administration or deliver medicine to an experimenter, for example, a patient, or by this compound administration or deliver medicine to a kind of in vitro tissue or cell, for example, from an experimenter's clone, this experimenter be for example one (for example there is disorder, described here a kind of disorderly), a kind of symptom of disorder, or the patient of the easy ill physique of disorderly tendency, to cure, recovery from illness, alleviate, alleviate, change, remedy, improve, improvement or affect this disorder, one or more symptoms of this disorder or disorderly tendency are (for example, prevent at least one symptom of this disorder or postpone the morbidity of at least one symptom of this disorder).
As used herein, treat disorderly compound significant quantity, or " treatment significant quantity " refers to when to an experimenter or a kind of cell list or multiple dose administration, an effective value of this compound in one or more symptoms of curing, alleviate, alleviate or improveing a kind of disorder.
As used herein, prevent disorderly compound significant quantity, or " the prevention significant quantity " of this compound refers to when to this experimenter's list or multiple dose administration, in prevention or postpone a kind of morbidity or recurrence of disorder, or the effective value of one in one or more symptoms of this disorder.
As used herein, term " experimenter " is intended to comprise the mankind or non-human animal.Exemplary human experimenter comprises have disorderly human patients (for example, a kind of disorder described here) or normal subjects.Term " non-human animal " in the present invention comprises all vertebratess, for example, nonmammalian (as chicken, Amphibians, Reptilia) and Mammals, as non-human primates, domestic and/or agriculturally useful animal, for example, sheep, milk cow, pig etc., and companion animals (dog, cat, horse etc.).
As used herein, term " CRM1 mediation disorder or illness " or " to CRM1 active relevant disorder or illness " meaning are the disease that plays a role therein of any CRM1 or other harmful illness.Therefore, an alternative embodiment of the invention relates to the seriousness for the treatment of or alleviate one or more diseases that CRM1 plays a role therein.Particularly, the present invention relates to a kind of method of seriousness for the treatment of or alleviating a kind of hyperplasia sexual disorder, the method comprises a kind of compound of the present invention or its a kind of pharmacy acceptable salt or its composition is delivered medicine to the patient who needs it.Other disorders are below being listed in detail.
In certain embodiments, the invention provides treatment method patient and expression p53, p73, p21, pRB, p27, I B, NF B, c-Abl, FOXO protein, COX-2 or active relevant a kind of disease, the method comprises a kind of compound described herein from a treatment significant quantity to this patient or its a kind of pharmacy acceptable salt or its composition that give.For example, provide in Mammals (comprising the mankind and non-human) method for the treatment of various cancers, the method to comprise at this kind of compound of the present invention or its a kind of pharmacy acceptable salt have been delivered medicine to the patient who needs it.The cancer of this class comprises: malignant hematologic disease (leukemia, lymphoma, myelomatosis, myeloproliferative disorder and myeloproliferative syndrome) and solid tumor (cancer is as prostate cancer, mammary cancer, lung cancer, colorectal carcinoma, carcinoma of the pancreas, kidney, ovarian cancer and soft tissue and osteosarcoma and mesenchymoma).Mammary cancer (BC) can comprise substrate sample mammary cancer (BLBC), three negative breast cancer (TNBC) and be that BLBC is again the mammary cancer of TNBC.In addition, mammary cancer can comprise duct carcinoma or the lobular carcinoma of invasive or Noninvasive, the tubular carcinoma of mammary gland, medullary substance cancer, mucinous carcinoma, papillary carcinoma, sieve shape cancer, male breast carcinoma, recurrent or metastatic breast cancer, Phylloides Tumors of The Breast, and paget disease of nipple (Paget ' s disease).
In certain embodiments, the invention provides the method for a kind of patient's for the treatment of struvite disorder, the method comprises a kind of compound of the present invention or its pharmacy acceptable salt is delivered medicine to this step of this patient.The struvite disorder of this class comprises rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitic syndrome (little, in and great vessels), arteriosclerosis, psoriatic and other skin inflammation sexual disorders (as pemphigus, pemphigoid, allergic dermatitis) and urticaria syndrome.
In certain embodiments, be amyotrophy to CRM1 active relevant disorder or illness, sacroiliitis (for example osteoarthritis and rheumatoid arthritis), ankylosing spondylitis, traumatic brain injury, Spinal injury, septicemia, rheumatism, carcinous atherosclerosis, type 1 diabetes, diabetes B, Leptospira renal tubal dysfunction, glaucoma, retinal diseases, aging, headache, pain, Complex regional pain syndrome, cardiac hypertrophy, muscle consume, katabolism disorder, fat, intrauterine growth retardation, hypercholesterolemia, heart trouble, chronic heart failure, local asphyxia/pour into again, apoplexy, cerebral aneurysm, stenocardia, tuberculosis, cystic fibrosis, acid source injury of lung, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren syndrome, hyaline membrane disease, ephrosis, renal glomerular disease, alcoholic liver disease, intestinal disease, peritonaeum endometriosis, tetter, nasal sinus, mesothelioma, lossless type ectoderm sexual abnormality-ID, Behcet's disease, incontinentia pigmenti, tuberculosis, asthma, Crohn's disease, colitis, eye allergy, ecphyaditis, Paget's disease, pancreatitis, tooth root periostitis, endometriosis, inflammatory bowel, struvite tuberculosis, silicon source property disease, sleep apnea, AIDS, HIV-1, autoimmune disorder, antiphospholipid syndrome, lupus, lupus nephritis, familial Mediterranean fever, heredity periodic fever syndrome, psychosocial stress disease, neuropathology disease, familial amyloid polyneuropathy, inflammatory neuropathy, Parkinson's disease, multiple sclerosis, alzheimer's disease, muscular dystrophy lateral sclerosis of spinal cord, huntington (Huntington) disease, cataract, or hearing loss.
In other embodiments, be head injury to CRM1 active relevant disorder or illness, uveitis, inflammatory pain, anaphylactogen brings out asthma, non-anaphylactogen brings out asthma, glomerulonephritis, ulcerative colitis, gangrenosum acne intestines colitis, there is the hyperimmunoglobulinemia D(HIDS of repetitiousness fever), TNF acceptor associated period syndrome (TRAPS), hidden hot albumen-associated period syndrome, Mu-Wei syndrome (the deaf amyloidosis of urticaria), familial cold urticaria, newborn infant's multisystem diseases associated with inflammation (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenositis (PFAPA syndrome), Blaw syndrome, suppurative sterility sacroiliitis, pyoderma gangraenosum, acne (PAPA), the interleukin 1 receptor antagonism factor lacks (DIRA), subarachnoid hemorrhage, multicystic kidney disease, transplant, organ transplantation, tissue transplantation, myelodysplastic syndrome, stimulator brings out inflammation, plant stimulatory material is brought out inflammation, elegant jessamine/laccol crude oil brings inflammation, chemical irritant brings out inflammation, bee sting brings out inflammation, sting brings out inflammation, sunburn, burn, dermatitis, endotoxemia, injury of lung, adult respiratory distress syndrome, alcoholic hepatitis, or the injury of the kidney being caused by parasitic infection.
Aspect other, the invention provides a kind of compound of the present invention or its a kind of pharmacy acceptable salt purposes for the manufacture of a kind of medicine, this medicine is used for the treatment of expression or the active relevant a kind of disease to p53, p73, p21, pRB, p27, IB, NFB, c-Abl, FOXO protein or COX-2.In certain embodiments, the invention provides a kind of compound of the present invention in a kind of purposes of manufacturing in a kind of medicine, this medicine is used for the treatment of cancer and/or tumprigenicity disorder, blood vessel generation, autoimmune disorder and/or disease, epigenetic, hormone disturbance and/or disease, virus disease, any in neurological sexual disorder and/or disease or ophthalmology disorder.
In certain embodiments, the invention provides a kind ofly for suppress the method for CRM1 biological material or patient, the method comprises the pharmacy acceptable salt of a kind of compound of the present invention or its a kind of pharmacy acceptable salt or composition is contacted or deliver medicine to this patient with this biological material.
Tumprigenicity disorder
Compound described here or composition can be in order to treat tumprigenicity disorder." tumprigenicity disorder " is a kind of disease or disorder, it is characterized by the cell with autonomous growth or replication, for example, and a kind of error state (ERST) or be characterized as the illness of proliferative cell growth.Exemplary tumour disorder comprises: cancer, sarcoma, metastatic disorder, for example, arise from the tumour of prostate gland, brain, bone, colon, lung, mammary gland, ovary and liver origin, the disorder of hematopoiesis tumprigenicity, for example, leukemia, lymphoma, myelomatosis and other malignant plasma cell disorder and metastatic tumo(u)r.Common cancer comprises: mammary cancer, prostate cancer, colorectal carcinoma, lung cancer, liver cancer and carcinoma of the pancreas.Use the treatment of this compound can be in the effective value of one, thereby improve at least one symptom of tumprigenicity disorder, for example, reduce cell proliferation, reduce tumor quality, etc.
The method of these disclosures is comprising, for example, the cancer of solid tumor, soft-tissue tumor and transfer thereof, together with in familial cancer syndrome as Li-Fo Meini syndrome (Li Fraumeni Syndrome), familial breast cancer and ovarian cancer (BRCA1 or BRAC2 sudden change) syndrome, and be useful in other prevention and treatment.The method of these disclosures is also useful in the non-solid carcinoma for the treatment of.The malignant tumour that exemplary solid tumor comprises Different Organs system (for example, sarcoma, gland cancer and cancer), as lung, mammary gland, lymph, gi tract (for example, colon) and genitourinary tract (for example, kidney, urothelium or tumor of testis), laryngocarcinoma, prostate cancer and ovarian cancer.Exemplary gland cancer comprises colorectal carcinoma, renal cell carcinoma, liver cancer, lung non-small cell carcinoma and carcinoma of small intestine.
The exemplary cancer of being described by National Cancer Institute comprises: acute lymphoblastic leukemia, adult; Acute lymphoblastic leukemia, children; Acute myeloid leukemia, adult; Adrenocortical carcinoma; Adrenocortical carcinoma, children; The lymphoma that AIDS-is relevant; The malignant tumour that AIDS-is relevant; Anus cancer; Astrocytoma, children's cerebellum; Astrocytoma, children's brain; Cholangiocarcinoma, outside liver; Bladder cancer; Bladder cancer, children; Osteocarcinoma, osteosarcoma/malignant fibrous histiocytoma; Brain stem neurospongioma, children; Cerebral tumor, adult; Cerebral tumor, brain stem neurospongioma, children; Cerebral tumor, cerebellar astrocytoma, children; Cerebral tumor, large cerebral astrocytoma/glioblastoma, children; Cerebral tumor, ependymoma, children; Cerebral tumor, medulloblastoma, children; Cerebral tumor, primitive neuroectodermal tumor on curtain, children; Cerebral tumor, optic nerve path and hypothalamic gliomas, children; Cerebral tumor, children (other); Mammary cancer; Mammary cancer and gestation; Mammary cancer, children; Mammary cancer, the male sex; Bronchial adenoma/carcinoid tumor, children; Carcinoid tumor, children; Carcinoid tumor, stomach and intestine; Cancer knurl, adrenocortical; Cancer knurl, islet cells; Unknown former cancer knurl; Central nervous system lymphoma, primary; Cerebellar astrocytoma, children; Large cerebral astrocytoma/glioblastoma, children; Cervical cancer; Children with cancer; Lymphocytic leukemia; Chronic myelocytic leukemia; Chronic myeloproliferative disorder; The clear cell sarcoma of stndon sheath; Colorectal carcinoma; Colorectal carcinoma, children; Skin T-cell lymphoma; Carcinoma of endometrium; Ependymoma, children; Epithelial cancer, ovary; The esophageal carcinoma; The esophageal carcinoma, children; Especially the tumour (Ewing's Family of Tumors) of Yin Shi family; Extracranial germ cell knurl, children; Extaagonactal perm celi tumors; Extrahepatic Bile Duct Carcinoma; Cancer eye, ophthalmo melanoma; Cancer eye, retinoblastoma; Carcinoma of gallbladder; Stomach (Gastric or Stomach) cancer; Stomach (Gastric or Stomach) cancer, children; Stomach and intestine carcinoid tumor; Gonioma, outside cranium, children; Gonioma, extragonadal; Gonioma, ovary; Gestational trophoblastic neoplasms; Neurospongioma, children's brain stem; Neurospongioma, children's children's vision path and hypothalamus; Hairy cell; Incidence cancer; Hepatocellular (liver) cancer, adult's (primary); Hepatocellular (liver) cancer, children's (primary); He Jiejin (family name) lymphoma, adult; He Jiejin (family name) lymphoma, children; In the He Jiejin of gestation time (family name) lymphoma; Hypopharyngeal cancer; The neurospongioma of hypothalamus and pathways for vision, children; Ophthalmo melanoma; Islet-cell carcinoma (endocrine pancreas); Kaposi sarcoma; Kidney; Laryngocarcinoma; Laryngocarcinoma, children; Leukemia, acute lymphoblastic leukemia, adult; Leukemia, leukemia, acute lymphoblastic, children; Leukemia, acute myeloid, adult; Leukemia, acute myeloid, children; Leukemia, chronic lymphocytic; Leukemia, chronic marrow; Leukemia, hair cell; Lip and oral carcinoma; Liver cancer, adult's (primary); Liver cancer, children's (primary); Lung cancer, non-small cell; Lung cancer, minicell; Lymphocytic leukemia, is grown up acute; Lymphocytic leukemia, children acute; Lymphocytic leukemia, chronic; Leukemia, AIDS-is relevant; Lymphoma, central nervous system (primary); Lymphoma, skin T-cell; Lymphoma, He Jiejinshi, adult; Lymphoma, He Jiejinshi, children; Lymphoma, He Jiejinshi is at gestation time; Lymphoma, non--He Jiejinshi (Non-Hodgkin's), adult; Lymphoma, non-Hodgkin's, children; Lymphoma, non-Hodgkin's is at gestation time; Lymphoma, primary central nervous system; Macroglobulinemia, Weir is stepped on this Tuo Mushi (Waldenstrom's); Male breast carcinoma; Malignant mesothelioma, adult; Malignant mesothelioma, children; Malignant thymoma; Medulloblastoma, children; Melanoma; Melanoma, intraocular; Merkel's cells cancer knurl; Mesothelioma, pernicious; There is the idiopathic pernicious transitivity squamous tumor colli of concealment; MEN syndrome, children; Multiple myeloma/plasmoma; Mycosis fungoides; Myelodysplastic syndrome; Myelocytic leukemia, chronic; Myelocytic leukemia, children acute; Myelomatosis, multiple; Myeloproliferative disorder, chronic; Nose and paranasal sinuses cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, children; Neuroblastoma; Non--He Jiejin lymphomas, adult; Non--He Jiejin lymphomas, children; Non--He Jiejin lymphomas is at gestation time; Nonsmall-cell lung cancer; Oral carcinoma, children; Oral cavity and lip cancer; Oropharynx cancer; Osteosarcoma/malignant fibrous histiocytoma of bone; Ovarian cancer, children; Epithelial ovarian cancer; Ovarian germ cell knurl; The tumour of ovary low potential malignancy potential; Carcinoma of the pancreas; Carcinoma of the pancreas, children; Carcinoma of the pancreas, islet cells; Nasal sinus and CARCINOMA OF THE NASAL CAVITY; Parathyroid carcinoma; Penile cancer; Pheochromocytoma; The upper primary neuroectodermal tumors of pineal gland and curtain, children; Pituitary tumor; Plasma cell tumor/multiple myeloma; Pleura pulmonary blastoma; Gestation and mammary cancer; Gestation and He Jiejin lymphomas; Gestation and non--He Jiejin lymphomas; Primary central nervous system lymphoma; Primary hepatocarcinoma, adult; Primary hepatocarcinoma, children; Prostate cancer; The rectum cancer; Nephrocyte (kidney) cancer; Renal cell carcinoma, children; Renal plevis and ureter, transition cell cancer; Cancer eye; Rhabdosarcoma, children; Salivary-gland carcinoma; Salivary-gland carcinoma, children; Sarcomata, the tumour of You Yinshijia; Sarcoma, Ka Boxishi (Kaposi's); Sarcoma (osteosarcoma)/malignant fibrous histiocytoma of bone; Sarcoma, rhabdosarcoma, children; Sarcoma, soft tissue, adult; Sarcoma, soft tissue, children; Sai Zhali (family name) syndrome; Skin carcinoma; Skin carcinoma, children; Melanoma (melanoma); Skin carcinoma, merkel's cells; Small cell lung cancer; Carcinoma of small intestine; Soft tissue sarcoma, adult; Soft tissue sarcoma, children; There is the idiopathic transitivity squamous tumor colli of concealment; Stomach (Gastric or Stomach) cancer; Stomach (Gastric or Stomach) cancer, children; Primitive neuroectodermal tumor on curtain, children; T cell lymphoma, skin; Carcinoma of testis; Thymoma, children; Thymoma, pernicious; Thyroid carcinoma; Thyroid carcinoma, children; Renal plevis and transitional cell carcinoma of ureter; Trophocyte's knurl, gestation; The cancer that original site is not clear, children; Rare children with cancer; Ureter and renal plevis, transitional cell carcinoma; Urethral carcinoma; Sarcoma of uterus; Carcinoma of vagina; Optic nerve path and hypothalamic gliomas, children; Carcinoma vulvae; Weir is stepped on this Tuo Mushi (Waldenstrom's) macroglobulinemia; And Wei Ermusishi tumour (Wilms'Tumor).According to method described here, can also treat or prevent above-mentioned cancer metastasis.
Cancer conjoint therapy
In certain embodiments, compound described here administration together with a kind of other cancer therapy.Exemplary cancer therapy comprises, for example: chemotherapy, targeted therapy (for example antibody therapy), enzyme inhibitors, immunotherapy, and hormonotherapy, and anti-angiogenic formation therapy.Each example of these treatments is provided below.
As used herein, when term " associating ", " associating " and relevant term refer to according to therapeutical agent of the present invention or continuous administration.For example, can be by a kind of compound of the present invention and another kind of therapeutical agent side by side or with the unit dosage that separates sequentially or to carry out administration together with single unit dosage.Therefore, the invention provides a kind of single unit dosage, this formulation comprises a kind of compound of the present invention, a kind of other therapeutical agent and a kind of pharmaceutically acceptable carrier, adjuvant or vehicle.
A kind of compound of the present invention and a kind of other therapeutical agent both (comprising in those compositions of other therapeutical agent a kind of as that describe hereinbefore) thus the amount that can produce a kind of single formulation with solid support material combination will depend on the main body for the treatment of and specific administering mode and change.Preferably, composition of the present invention should be mixed with like this so that can be by the dosed administration of a kind of compound of the present invention between 0.01-100mg/kg body weight/day.
Chemotherapy
In certain embodiments, compound described here is carried out together with a kind of chemotherapy to administration.Chemotherapy is to use pharmacological agent cancer, and these medicines can destruction of cancer cells." chemotherapy " refers to the impact cytotoxic drug of the cell of division rapidly conventionally in the ordinary course of things, contrary with targeted therapy.Chemotherapy drugs divides with multiple possible approach interference cell, for example, disturb the separation of the chromosomes that copies or newly form of DNA.Although the specificity of some degree can be repaired (and normal cell conventionally can) to DNA damage from kinds cancer cell anergy power, chemotherapeutic most of forms all target rapidly division cell and be not that specificity is for cancer cells.
The example that is used in the chemotherapeutic in cancer therapy comprises, for example, metabolic antagonist (for example, folic acid, purine and pyrimidine derivatives) and alkylating agent (for example, mustargen, nitrosourea, platinum, alkyl sulfonate esters, hydrazine, triazene, aziridine, spindle poison, cytotoxic agent, topoisomerase enzyme inhibitor and other).Exemplary reagent comprises aclarubicin, actinomycin, alitretinoin (Alitretinoin), hexamethyl melamine, aminopterin, amino-laevulic acid, amrubicin, amsacrine, anagrelide, white arsenic, Asparaginase, atrasentan, Belotecan, bexarotene, bendamustine, bleomycin, Velcade, busulfan, camptothecine, capecitabine, Carboplatin, carboquone, carmofur, carmustine, celecoxib, Chlorambucil, mustargen, cis-platinum, CldAdo, Clofarex, chrysanthemum Ou Wenshi enzyme (Crisantaspase), endoxan, cytosine arabinoside, Dacarbazine, gengshengmeisu, daunorubicin, Decitabine, Omaine, docetaxel, Zorubicin, Efaproxiral, department of Erie is not, elsamitrucin, enocitabine, epirubicin, estramustine, Etoglucid, Etoposide, azauridine, fludarabine, Fluracil (5FU), fotemustine, gemcitabine, Gliadel implants, hydroxycarbamide (Hydroxycarbamide), hydroxyurea (Hydroxyurea), idarubicin, ifosfamide, irinotecan, irofulven, ipsapirone, La Luotasai (Larotaxel), folinic acid, Mycocet, daunorubicin liposome, lonidamine, lomustine, lucanthone, Mannosulfan, masoprocol, L-sarcolysin, purinethol, mesna, methotrexate, methylamino ketone valerate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, S 254, Nidran, Ao Limosen (Oblimersen), homoharringtonine (Omacetaxine), Ao Tasai, oxaliplatin, taxol, Pegaspargase, pemetrexed, pentostatin, pirarubicin, China fir fine jade, Plicamycin, porfimer sodium, prednimustine, Procarbazine, Raltitrexed, ranomustine, rubitecan, Sa Pacitabini (Sapacitabine), semustine, adenovirus carrier alignment code gene, his platinum (Strataplatin) of this azoles, streptozocin, talaporfin, Tegafur uridylic, temoporfin, Temozolomide, teniposide, for Si Tasai (Tesetaxel), testolactone, tetranitrate, thiophene is for group, tiazofurine, Tioguanine, for pyrrole method Buddhist nun, Hycamtin, ET-743, triaziquone, Persistol, three molybdenums (Triplatin), vitamin A acid, Treosulfan Leo, Z-4828, Uramustine, valrubicin, Visudyne, vinealeucoblastine(VLB), vincristine(VCR), vindesine, Vinflunine, Vinorelbine, Vorinostat, zorubicin and other cytostatic agent described here or cytotoxic agent.
The effect using together due to some medicines is greater than independent use, therefore often provides two kinds or more kinds of medicine simultaneously.Frequently, by two kinds or more kinds of chemotherapeutic as combination chemotherapy.In certain embodiments, these chemotherapeutics (comprising combinatorial chemistry therapy) can be combined use with a kind of compound described here.
Targeted therapy
Targeted therapy comprises the specific medicament of down-regulation protein using for cancer cells.Small molecules targeted therapy medicine the inhibitor normally sudden change within cancer cells, that cross the enzymatic structure territory of key albumen that express or other.Significant example is tyrosine kinase inhibitor, as Axitinib, bosutinib, AZD2171, moral Sa for Buddhist nun (desatinib), two sieve for Buddhist nun (erolotinib), imatinib, Gefitinib, lapatinibditosylate, come him for you, AMN107, SU5416, Xarelto, Sutent and ZD6474, with cyclin-dependent kinase inhibitor, as many in flavones pyrrole (Alvocidib) and Se Lisi Carlos Kleiber (Seliciclib).Monoclonal antibody therapy is another strategy, and wherein, this therapeutical agent is a kind of antibody, is attached to this antibodies specific a kind of albumen on cancer cells surface.Example comprises the anti-HER2/neu antibody Herceptin being typically used in mammary cancer and be typically used in anti-CD 20 antibodies Rituximab and the tositumomab in multiple B-cell malignancies.Other exemplary antibody comprises Cetuximab, Victibix, Herceptin, alemtuzumab, rhuMAb-VEGF, Edrecolomab and gemtuzumab.Exemplary fusion rotein comprises VEGF Trap and denileukin diftitox.In certain embodiments, targeted therapy can with a kind of compound described here, 2001) be used in combination for example, imatinib mesylate (Gleevec) (Vignari(Wigner is auspicious) and Wang(king).
Targeted therapy can also comprise the small-molecular peptides as " homing device (homing devices) ", and this small-molecular peptides can be incorporated into cell surface receptor or affects tumour extracellular matrix around.If nucleic decays at adjacent cells, the radionuclide being for example attached to, on these peptides (, RGD) finally kills cancer cells.An example of this type of therapy comprises
Figure BDA0000484103910001192
Vasculogenesis
Compound described here can be used to treatment or prevention disease or the disorder relevant to vasculogenesis.The disease relevant to vasculogenesis comprises cancer, cardiovascular disorder and macular degeneration.
Vasculogenesis is a kind of physiological processes, relates to the growth of new blood vessel from existing blood vessel.Vasculogenesis is a kind of at g and D, together with in wound healing and the normal and vital process in granulation tissue.But it is also tumour cell changes malignant state into a basic step from dormant state.Vasculogenesis can be a target for resisting disease, these diseases be characterized as little vascularization or abnormal vascular system.
The using of specific compounds that can suppress or induce neovascularity in vivo to be set up can help to resist this type of disease.The blood vessel existing at the position that should not exist can affect a kind of mechanical characteristic of tissue, increases the possibility of exhaustion.The shortage of the blood vessel in injury repairing or the active tissue of other metabolism can suppress reparation or other basic function.Some diseases, if ischemic chronic trauma is the result of exhaustion or vasculogenesis deficiency, and can treat by local vessel expansion, bring new nutrient substance to thus these positions, thereby promote to repair.Other disease, as relevant in the macula lutea degeneration of age-dependent, can cause by local vessel expansion, thereby disturb normal physiological processes.
Vascular endothelial growth factor (VEGF) has been proved to be vasculogenesis, thereby in given vasoganglion, increases the main contributions person of microvascular number.It is physiological responses in a kind of main component of motion (exercise) that VEGF raises, and its effect in vasculogenesis under a cloud be a kind of possible treatment in blood vessel injury.In vitro study clearly proves, VEGF is a kind of effective stimulator of vasculogenesis, because under the existence of this somatomedin, plate-like endotheliocyte will hyperplasia and divided a word with a hyphen at the end of a line, thereby finally forms similar microvascular tubular structure.
Tumour for example, by the different somatomedin (, VEGF) of secretion, induction of vascular growth (vasculogenesis).Somatomedin can induce capillary blood vessel to grow in tumour as bFGF and VEGF, and some investigators suspect, this supplies desired nutrient substance, thereby allows tumour expansion.
Vasculogenesis representative is for a fabulous therapeutic goal for the treatment of cardiovascular disease.This is a kind of effective physiological processes based on natural way, and by this way, our health, in response to the minimizing that is supplied to vital organ blood, in other words, overcomes ischemic damage thereby generate new collateral vessel.
The perviousness enhancing causing in blood vessel except stimulating vasculogenesis is expressed in crossing of VEGF.In moist macular degeneration, VEGF causes that capillary blood vessel hyperplasia enters in retina.Because the increase of vasculogenesis also causes edema, blood and other retina fluid leaks enter retina, thereby cause blind.
Anti-angiogenic therapy can comprise that the kinase inhibitor of target vascular therapy endothelial cell growth factor (ECGF) (VEGF) is as Sutent, Xarelto, or monoclonal antibody or acceptor " bait " for VEGF or vegf receptor comprise rhuMAb-VEGF or VEGF-Trap, or Thalidomide or its analogue (Revlimid, amber agate dynamics amine (pomalidomide)), or target non--medicament of the former target of VEGF blood vessel is as fibroblast growth factor (FGF), angiogenin or angiostatin or endostatin.
Epigenetics
Compound described here can be used to treatment or prevention disease or the disorder relevant to epigenetics.Epigenetics is the research of the hereditary change of the phenotype that caused by the mechanism except the change based on DNA sequence dna or genetic expression.The process that example is cytodifferentiation that epigenetic in eukaryote changes.In morphogenesis process, stem cell becomes the different clones of embryo, goes forward side by side and becomes completely the cell of differentiation.In other words, a single fertilized egg cell becomes many kinds of cell types, comprises neurone, myocyte, epithelial cell, blood vessel etc., those that continue to divide as it.It suppresses other genes simultaneously and realizes this differentiation by activating some genes.
In the time of cell fission, epigenetic variation is kept.Most epigenetic variation occurs over just in the life-cycle processes of individual organism, and still, if caused the DNA mutation that causing fertilization in sperm or ovum, some epigenetics change and will be genetic to the next generation by a generation so.Concrete epigenetic process comprises paramutation, add bookmark (bookmarking), add trace, gene silencing, x chromosome inactivation, position effect, reprogramming, turn virus (transvection), maternal effect, carcinogenesis process, teratogenic factor multiple effect, histone modification and heterochromatic adjusting and affect parthenogenesis and clone's technical limitation.
The exemplary disease relevant to epigenetics comprises (Coffin-Lowry) syndrome in ATR-syndrome, Fragile X syndrome, ICF syndrome, angel people's syndrome (Angelman ' s syndrome), Pu Ruide-Willie Cotard (Prader-Wills syndrome), BWS, Rett syndrome, α-thalassemia, cancer, leukemia, Robinstein-Typee (Rubinstein-Taybi) syndrome and Kao Feiyin-Lao.
First human diseases relevant to epigenetics is cancer.Investigator finds to have recently from similar patient's healthy tissues DNA methylation still less from patient's the pathological tissues of suffering from colorectal carcinoma.Because methylated gene is typically closed, the disappearance of DNA methylation can cause unusual high gene activation by changing chromatinic arrangement.On the other hand, the work of the tumor suppressor gene of protectiveness is cancelled in the too much meeting that methylates.
DNA methylation occurs in CpG site, and in Mammals, most of CpG cytosine(Cyt) is methylated.But, there is DNA section at promotor near zone, these sections in normal cell, have concentration degree higher, unmethylated CpG site (being called CpG island).These CpG islands become and extremely methylate in cancer cells, cause thus should be reticent the closing of gene.Thisly be the mark that changes of the epigenetic that occurs in tumour extremely and occur in early days at cancer development.The supermethylation on CpG island can cause tumour by cutting off tumor suppressor gene.In fact, the change of these types is more general than DNA sequence dna sudden change in human cancer.
In addition, can not change DNA sequence dna although epigenetic changes, they can cause sudden change.These cause cancer familial or the only about half of of genetic gene be closed by methylating.The great majority of these genes normally suppress tumour and form and help DNA plerosis, comprise O6-Methylguanine DNA-Methyltransferase (MGMT), MLH1 cyclin dependent kinase inhibitor 2B(CDKN2B) and RASSF1A.For example, the supermethylation of MGMT promotor causes the increase of G-to A-sudden change number.
Supermethylation also can cause the unstable of micro-satellite, and micro-satellite is the DNA sequence dna of repetition.Micro-satellite ubiquity in normal individual, and they are made up of the dinucleotides CA repeating conventionally.The promotor of DNA-repair gene MLH1 excessively methylates and can make microsatellite instability and by its prolongation or shortening.The unstable of micro-satellite and many related to cancer, comprise colorectal carcinoma, carcinoma of endometrium, ovarian cancer and cancer of the stomach.
Fragile X syndrome is the most normal hereditary dysnoesia, especially in the male sex.Two kinds of sexes all can be subject to the impact of this illness, but because the male sex only has an X chromosome, the X of a fragility will be more serious on their impact.Really, Fragile X syndrome incidence is roughly in the male sex 1/4000, and in women 1/8000.Suffer from this syndromic people and have serious dysnoesia, the speech of delay is grown, and " class autism " behavior.
The appearance that fragile X mental retardation seems under the microscope from the X chromosome part that comprises gene unconventionality is gained the name; It conventionally presents and seems hanging and be easy to fragmentation by single line.This syndrome is at FMR1(fragile X mental retardation 1 by one) extremely causing in gene.The people who does not suffer from fragile X mental retardation has the repetition of 6 to 50 trinucleotide CGG in their FMR1 gene.But, there is the individuality that exceedes 200 repetitions and there is a kind of full mutation, and they show this syndromic symptom conventionally.Too much CGG causes becoming methylated on CpG island, FMR1 gene promoter area; And under normal circumstances, their right and wrong are methylated.This methylating closed this gene, makes this FMR1 gene stop producing a kind of important albumen that is called fragile X mental retardation albumen.The disappearance of this specific proteins has caused Fragile X syndrome.Although given a lot of concern of CGG amplification sudden change that fragile X causes, it is this syndromic real reason that the epigenetic that methylates relevant to FMR1 changes.
Fragile X syndrome be not unique relate to backwardness that epigenetic changes relevant disorder.(Coffin-Lowry) syndrome, Pu Ruide-Willie Cotard (Prader-Wills syndrome), angel people's syndrome, Bai-Wei syndrome (Beckwith-Wiedemann), ATR-X syndrome and Rett syndrome in other this type of illness bag Robinstein-Typee (Rubinstein-Taybi) syndrome and Kao Feiyin-Lao.
Epigenetics therapy comprises the enzyme of controlling epigenetic modification; particularly the inhibitor of dnmt rna and histone deacetylase is (for some malignant tumours; they show good antitumorigenic effect), together with antisense oligonucleotide and siRNA.
Immunotherapy
In certain embodiments, compound described here is carried out together with a kind of immunotherapy to administration.Tumour immunotherapy refers to a different set of therapeutic strategy that is designed to induce patient's autoimmunization system counter tumour.For generation of immune response, the method in antineoplastic modern times is comprised for BCG immunotherapy, prostate cancer vaccine Pu Luowenqi (Provenge) in the blood vessel of superficial bladder cancer and uses Interferon, rabbit and other cytokines at renal cell carcinoma and melanoma patient induce immune response.
Allochthonous hematopoietic stem cell transplantation can be considered a kind of form of immunotherapy, because in transplanting-p-tumor effect, the immunocyte of donor will often be attacked tumour.In certain embodiments, these immunotherapy agent can be used with a kind of compound combination described here.
Hormonotherapy
In certain embodiments, compound described here is carried out together with a kind of hormonotherapy to administration.The growth of certain cancers can suppress by providing or block hormone.The common example of hormone-sensitive type tumour comprises mammary cancer and the prostate cancer of some type, together with the leukemia in response to vitamin A acid/vitamin A acid of some type.Removal or blocking-up oestrogenic hormon or testosterone are usually a kind of important additional treatments.In some cancer, give and hormone agonist, if progestogens can be that treatment is upper useful.In certain embodiments, these hormonotherapy agent can be combined use with a kind of compound described here.
Inflammation and autoimmune disorder
Compound described here can be being especially used to treatment or prevention disease or the disorder relevant to inflammation in the mankind and other Mammals.Compound described here can inflammation start morbidity before, in or administration afterwards.In the time prophylactically using, these compounds were preferably provided before any inflammatory response or symptom.Give these compounds and can prevent or weaken inflammatory response or symptom.Exemplary inflammatory illness comprises, for example, and multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, spondyloarthropathy, other seronegative inflammatory arthritis, rheumatic polymyopathy, various vasculitiss (for example, giant cell arteritis, ANCA+ vasculitis), urarthritis, systemic lupus erythematous, juvenile arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (for example, insulin-dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel, irritable bowel syndrome, clone disease (Crohn's disease), mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatism (acute or chronic), multiple organ injury's syndrome (for example, Secondary cases septicemia or wound), myocardial infarction, the stagnant property arteriosclerosis of fat, apoplexy, reperfusion injury (for example,, due to cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, thermal damage (, sunburn), necrotizing enterocolitis, the syndrome that granulocyte infusion is relevant, and/or siogren's syndrome (Sjogren's syndrome).Exemplary skin inflammation venereal disease disease comprises, for example, and eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriatic and there is the tetter of acute inflammatory component.
In another embodiment, a kind of compound described here or method can be used for the treatment of or prevent transformation reactions and respiratory condition, comprise asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen intoxication, pulmonary emphysema, chronic bronchitis, adult respiratory distress syndrome and any chronic obstructive pulmonary disease (COPD).These compounds can be used to treat chronic hepatitis and infect, and comprise hepatitis B and hepatitis C.
In addition, compound described here or method can be used for the treatment of autoimmune disease and/or the inflammation relevant to autoimmune disease as organ-tissues autoimmune disorder (for example, Raynaud's syndrome (Raynaud's syndrome)), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, septicemia, psoriatic, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosus, Addison's disease (Addison's disease), autoimmunization polyadenopathy (also referred to as autoimmune polyglandular syndrome) and Gray Fu Shi disease (Grave's disease).
In a specific embodiment, these compounds described herein can be used for treating multiple sclerosis.One concrete aspect in, the compound that is used for the treatment of multiple sclerosis is compound 1:(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone.
Combination treatment
In certain embodiments, a kind of compound described here can be individually or with other the compound combination ground administration that is useful on treatment or preventing inflammation.Exemplary anti-inflammation agent comprises, for example, steroid (for example, hydrocortisone, cortisone, fluohydrocortisone, prednisone, 6[α]-methylprednisolone, triamcinolone, Betamethasone Valerate or dexamethasone), nonsteroidal anti-inflammatory drug (NSAIDS) (for example acetylsalicylic acid, Paracetamol, Tolmetin, Ibuprofen BP/EP, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, R-ETODOLAC or nimesulide).In another embodiment, other therapeutical agent is microbiotic (for example, vancomycin, penicillin, amoxycilline Trihydrate bp, Ampicillin Trihydrate, cefotaxime, ceftriaxone, Cefixime Micronized, Rifampin metronidazole, Vibravenos or Streptomycin sulphate).In another embodiment, other therapeutical agent is PDE4 inhibitor (for example, roflumilast or rolipram).In another embodiment, other therapeutical agent is antihistaminic's (for example, cyclizine, hydroxyzine, promethazine or diphenhydramine).In another embodiment, other therapeutical agent is antimalarial drug (for example, Artemisinin, Artemether, Artesunate, chloroquini phosphas, Mefloquine Hydrochloride, Doxycycline Hyclate, Tirian, atovaquone or halofantrine).In one embodiment, other compound is flexing gram solidifying α.
The other example of anti-inflammatory agent comprises, for example, and Aceclofenac, acemetacin, e-kharophen caproic acid, Paracetamol, acetaminosalol, Acetanilide, acetylsalicylic acid, S-adenosylmethionine, Warner-Lambert), Modrasone, alfentanil, alphasone, Allylprodine, alminoprofen, aloxiprin, alphaprodine, Rumasal (acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-AMINO-4-PICOLINE, aminopropylon, pyramidon, amixetrine, Salicylate ammonium, Ampiroxicam, Amtolmetin Guacil, anileridine, quinizine, antrafenine, Azapropazone, beclometasone, Bendazac, Benorilate, Compd 90459, Benzpiperylone, benzydamine, benzylmorphine, bermoprofen, Betamethasone Valerate, Betamethasone Valerate-17-valerate, Bezitramide, [α]-bisabolol, Bromfenac, asepsin, 5-bromic acid ester, bromosaligenin, bucetin, bucloxonic acid, bucolome, budesonide, bufexamac, bumadizon, buprenorphine, Butacetin, butibufen, butorphanol, Carbamzepine, etymide, carprofen, carsalam, trichloro-butyl alcohol, Chloroprednisonum, chlorthenoxazine, choline salicylate, Viophan, cinmetacin, Wy-15705, clidanac, clobetasol, clocortolone, R-3959, Clonitazene, Sch-10304, Clopirac, Syntestan, cloves (clove), morphine monomethyl ether, Eucodin, codeine phosphate, codeine sulfate, cortisone, cropropamide, cropropamide, Crotethamide, cyclazocine, deflazacort, boldenone, Desomorphine, Hydroxyprednisolone Acetonide, desoximetasone, dexamethasone, dexamethasone-21-γ-picolinic acid salt, dexoxadrol, dextromoramide, Propoxyphene, Propoxyphene, Wy-16225, diampromide, Heroin, diclofenac, difenamizole, Z-876, diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol acetate, Paramorphan, dihydroxyaluminum aspirin, dimenoxadol, Dimepheptanol, Takaton, dioxaphetyl butyrate, dipipanone, general former times of Supreme Being is for (diprocetyl), Sulpyrine, ditazole, Droxicam, nron, enfenamic acid, glycyrrhetinic acid, epirizole, eptazocine, etherylate, Ethoxybenzamide, ethoheptazine, etoxazene, Ethylmethylthiambutene, Ethylmorphine, R-ETODOLAC, etofenamate, etonitazene, Eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, Zentinic, floctafenine, Fluazacort, flucloronide, Flufenamic Acid, aniprime, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocortolone, fluoresone, fluorometholone, fluperolone, flupirtine, fluprednidene, fluprednisolone, Tormosyl, flurrenolone, flurbiprofen, fluticasone, formocortal, Fosfosal, gentisinic acid, R 1707, indomethacin glucosamide, glycol salicylate, Guaiazulene, halcinonide, ulobetasol, halometasone, Topicon, heroine, hydrocodone, hydrocortamate, hydrocortisone, hydrocortisone acetic ester, hydrocortisone succinate, hydrocortisone half amber ester, hydrocortisone 21-lysine salt, hydrocortisone cipionate, hydromorphone, hydroxypethidine, ibufenac, Ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, Isofezolac, isoflupredone, 9-fluorine Ultracortene-H-21-acetic ester, different draw piece (isoladol), isomethadone, isonixin, Isoxepac, isoxicam, ketobemidone, Ketoprofen, ketorolac, p-Lactylphenetidine, lefetamine, levallorphan, Dromoran, Levophenacylmorphan, Lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, Zpoflogin, mefenamic acid, meloxicam, Pethidine, meprednisone, meptazinol, aminosallcylic acid, methobenzmorphan, methadone, Levopromazine, medrat, Methylprednisolone Acetate, methylprednisolone, medrat Se Ernai (methylprednisolone suleptnate), metiazinic acid, Metofoline, metopon, mofebutazone, N-22, Mometasone, R-445, morphine, Srm-Rhotaard, morphine sulfate, Morpholine Salicylate, Peronine myristate, nabumetone, nalbuphine, nalorphine, 1-Naphthyl Salicylate, Naproxen Base, Papaverine, nefopam, nicotinic acid morphine ester, neopiran, niflumic acid, nimesulide, 5'-nitro-2'-propoxy-Acetanilide, norlevorphanol, Normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacin, Taisho), oxycodone, oxymorphone, Tacote, Papaveretum, paramethasone, Renytoline, parsalmide, pentazocine, perisoxal, Phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, Phenopyrazone, phenomorphan, Vesipyrin, BUTE, salol, fenyramidol, Piketoprofen, piminodine, pipebuzone, Piperylone, pirazolac, Pirinitramide, piroxicam, pirprofen, Y-8004, prednicarbate, dehydrohydro-cortisone, prednisone, W-4869, prednylidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, Propoxyphene, Propyphenazone, Soz 43-715, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, saligenin, salicylic amide, Salicylamide O-acetic Acid, Whitfield's ointment, salicylsulfuric acid, salsalate, Salverine, simetride, sufentanil, sulfasalazine, sulindac, superoxide-dismutase, sutoprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, Tetrrine, thiazolinobutazone, tiaprofenic acid, tiaramide, Tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, U-26225A, triamcinolone, Triamcinolone Acetonide, Tuo Peixin, Z-424, xenbucin, ximoprofen, zaltoprofen and Zomepirac sodium salt.
In one embodiment, a kind of compound described here can with a kind of be used for the treatment of or selective COX-2-2 inhibitor of preventing inflammation together with administration.Exemplary selective COX-2-2 inhibitor comprises, for example, and deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, L-791456 and Lu meter Kao former times.
In certain embodiments, the compound providing and a kind of anthracycline antibiotics or a kind of Topo II inhibitor Combined Preparation.In certain embodiments, the compound providing and Zorubicin (Dox) Combined Preparation.In certain embodiments, the compound providing and Velcade (and comprising more widely Ka Feizuo meter (carfilzomib)) combination medicine-feeding.Unexpectedly, having been found that the compound providing is combined with Dox or Velcade causes a kind of synergistic effect (that is, be greater than addition).
Virus infection
Compounds and methods for described here can be used to treatment or prevention especially in the mankind and relevant disease or the disorder of virus infection in other Mammalss.Compound described here can virus infection start morbidity before, in or administration afterwards.In the time prophylactically using, these compounds were preferably provided before any virus infection or its symptom.
Exemplary virus disease comprises febris acuta pharyngitis, pharyngo-conjunctival fever, viral keratoconjunctivitis, child's gastroenteritis, Coxsackie virus infection (Coxsackie infections), infectious mononucleosis, Burkitt lymphoma (Burkitt lymphoma), acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, primary HSV-1 infects (primary HSV-1infection) (for example, children's gingivostomatitis, adult's tonsillitis and pharyngitis, keratoconjunctivitis), latent HSV-1 infects (latent HSV-1infection) (for example, herpes labialis and cold sore), primary HSV-2 infects, latent HSV-2 infects, aseptic meningitis, infectious mononucleosis, cytomegalic inclusion disease, Ka Boxishi sarcomata, multicenter castleman disease, lymphoma primary effusion, AIDS, influenza, Lay syndrome (Reye syndrome), measles, PIE, parotitis, hyperplasia epithelial lesion is (for example, common, smooth, the sole of the foot and anogenital wart, laryngeal papillomatosis, epidermodysplasia verruciformis), cervical cancer, squamous cell cancer, croup, pneumonia, bronchiolitis, common cold, poliomyelitis, rabies, flu syndrome, serious bronchiolitis and pneumonia, Rubella, congenital rubella, varicella, and zoster.
Exemplary viral pathogen comprises adenovirus, Coxsackie virus, dengue virus, meningitis virus, epstein-barr virus (EB), hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex types 1 virus, herpes simplex types 2 virus, cytomegalovirus, 8 type nerpes vinrus hominises, human immunodeficiency virus, influenza virus, Measles virus, mumps virus, human papillomavirus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, german measles virus, varicella zoster virus, west nile virus, dengue virus, and yellow fever virus.Viral pathogen can also comprise the virus that those cause resistance virus infection.
Antiviral drug is the medicament that a class is used for the treatment of virus infection specifically.Antivirus action is one of three kinds of mechanism normally: the ability of viral interference invasion and attack target cell (for example, amantadine, Rimantadine and pleconaril), viral synthetic inhibition (for example, nucleoside analog, for example, acyclovir and zidovudine (AZT)) and the viral inhibition (for example, zanamivir and oseltamivir) discharging.
Ophthalmology
Compound described here can be used to treatment or the disorder of prevention ophthalmology.Exemplary ophthalmology disorder comprises macular edema (macular edema diabetes and ND), moist and the dryness sex change of the macula lutea relevant with the age, Age-related disciform degeneration of macula, cystoid macular edema, palpebral edema, retinal edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative detachment of retina, keratohelcosis, conjunctival ulcer, nummular keratitis, the ophthalmic diseases relevant to histanoxia or local asphyxia, retinopathy of prematurity, PDR, polypoidal choroidal vasculopathy in Chinese patients, retinal angiomatous proliferation, occlusion of retinal artery, retinal vein occlusion, hat Ci Shi disease, familial exudative vitreoretinopathy, pulseless (Takayasu's disease pulseless disease), periphlebitis of retina, antiphospholipid antibody syndrome, leukemic retinopathy, HSV, macroglobulinemia, Interferon, rabbit-relevant retinopathy, hypertensive retionpathy, radiation retinopathy, corneal epithelial stem cells lacks and cataract.
Neurodegenerative disease
Neurodegeneration is the forfeiture gradually for neuronic structure or function, comprises the containing property term of neuronal death.Comprise parkinsonism, Alzheimer's disease and Heng Tingdunshi disease many neurodegenerative diseases be the result of neurodegenerative process.Along with progress, the disease relevant with these diseases demonstrates each other many similaritys on subcellsular level.The similarity of these discoveries provides hope for the further treatment that can improve various diseases simultaneously.There are a lot of similarities comprising between the different neurodegenerative disorders of atypical assembly together with inducibility necrocytosis.
Alzheimer be characterized as neurone and the ganglionic loss in cortex and some subcortical areas.This loss causes comprising temporal lobe and top, and the serious atrophy of the involved area of the sex change of the part of volume cortex and cingulate gyrus.
Huntington's disease causes proliferation of astrocytes and the neuronic loss of middle sour jujube.The neuronic type that brain region comprises according to their structure and they, because their lost cell and sizes of reducing and impaired cumulatively.Involved area is mainly at striatum, but also has in volume cortex and temporo cortex.This striatal SubN transfer control signal is to this pallidum, and this pallidum starts and adjustment movement.Signal from SubN is more weak, causes thus motion to start and the minimizing regulating, thereby causes the motion disorder of typicalness.The exemplary treatment for Huntington's disease comprises tetrabenazine, neural sedative, benzodiazepine, amantadine, remacemide, valproic acid, selective serotonin reuptake inhibitor (SSRIs), mirtazapine and antipsychotic.
In Parkinson's disease, can be included in the abnormal accumulation of the albumen alpha-synapse nucleoprotein that is bonded to ubiquitin in damaged cell by the mechanism of its loss brain cell.This alpha-synapse nucleoprotein-ubiquitin complex body cannot guiding protein enzyme body.This albumen accumulation has formed the protein cell matter inclusion that is called Louis body.Up-to-date disease pathogenesis research shows to depend on by the death of the dopaminergic neuron of alpha-synapse nucleoprotein the textural defect of the albumen transportation between the organoid-endoplasmic reticulum main at two kinds (ER) and golgi body.In animal model, some albumen is this defect being caused by alpha-synapse nucleoprotein as Rab1 can reverse.Exemplary Parkinson's disease therapy comprises levodopa, dopamine agonist is as comprised bromocriptine, pergolide, pramipexole, Ropinirole, Piribedil, Cabergoline, Apomorphine and methylergol carbamide, DOPA decarboxylation inhibitor, MAO-B inhibitor is as selegiline and rasagiline (selegilene and rasagilene), Anticholinergics and amantadine.
Amyotrophic lateral sclerosis (ALS/ Lu Jia RD (Lou Gehrig ' s Disease)) is the optionally disease of directed sex change of a kind of motor neuron.Exemplary ALS therapy comprises Riluzole, baclofen, diazepam, Trihexyphenidyl and amitriptyline.
Other exemplary neurodegenerative therapy comprises antisense oligonucleotide and stem cell.
Other disorder
Compound described here and composition can also be used for the treatment of abnormal structure's growth and Fibrotic disorder, comprise swelling property cardiomyopathy, hypertrophic neuropathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis and other kidney disorders.
The present invention has been described in disclosure above generally.By obtaining more complete understanding with reference to following specific examples.These examples are only described as illustrative object, and are not intended to limit the scope of the invention.Along with advising or give situation easily, consider the variation of form and equivalent substituting.Although used specific term at this, these terms are intended to illustrative meaning and are not for restrictive object.
Illustration
Abbreviation
Atm atmosphere
Aq. water-based
BINAP 2, two (diphenylphosphino)-1 of 2'-, 1'-binaphthylyl
Uncle Boc-butoxy carbonyl
CDI N, N '-carbonyl dimidazoles
DCC N, N-dicyclohexylcarbodiimide
DCM methylene dichloride
DBU diaza (1,3) two ring [5.4.0] undecanes
DEA N, N-diisopropyl ethyl amine
DIBAL-H diisobutylaluminium hydride
DIC N, N '-DIC
DMAP N, N-dimethyl-4-aminopyridine
DMF dimethyl formamide
DMSO methyl-sulphoxide
DPPF Diphenyl phosphino ferrocene
EA ethyl acetate
EDCI N-[3-(dimethylamino) propyl group]-N'-ethyl-carbodiimide hydrochloride
EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
Et 2o diethyl ether
EtOAc ethyl acetate
EtOH ethanol
EtI iodoethane
Et ethyl
Fmoc 9-fluorenylmethyloxycarbonyl
H hour
HetAr heteroaryl
HOBt N-hydroxybenzotriazole
HBTU O-(benzotriazole-1-yl)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
HPLC high performance liquid chromatography
LAH lithium aluminum hydride
LCMS HPLC mass spectrum
MCPBA m-chloro-benzoic acid
MeCN acetonitrile
MeOH methyl alcohol
Min minute
MeI methyl iodide
MeMgCl methylmagnesium-chloride
Me methyl
N-BuLi 1-butyllithium
NaOAc sodium acetate
NMR nucleus magnetic resonance
NMP N-Methyl pyrrolidone
NBuLi 1-butyllithium
O.n. spend the night
RBF round-bottomed flask
RT, rt, r.t. room temperature
T3P propyl phosphonous acid acid anhydride (can from Archimica(Archie meter Ka company) obtains
TEA triethylamine
THF tetrahydrofuran (THF)
NBu normal-butyl
OMs mesylate or methane sulfonates
OTs tosilate, tosylate or 4-tosylate
PCC pyridinium chlorochromate
PPTS p-toluenesulphonic acids pyridine
TBAF tetrabutylammonium
PTsOH p-toluenesulphonic acids
SPE Solid-Phase Extraction (generally including for mini chromatographic silica gel)
Sat. saturated
GP protecting group
Mins minute
By the description hereinafter of this class process; should be understood that, in appropriate circumstances, will add suitable blocking group; and the mode to be easy to be understood by the those of ordinary skill in organic synthesis field is removed from different reactants and intermediate subsequently.For using the conventional procedure of this type of blocking group to be described in together with the example of suitable blocking group; for example; " blocking group in Protective Groups in Organic Synthesis(organic synthesis) "; T.W.Green(Green); P.G.M.Wuts(Watts); Wiley-Interscience(Willie press), New York, in (1999).What will also be understood that is, by chemical operation, a group or substituting group are converted into another group or substituting group, can be on any intermediate or end product, under the route of synthesis that forms end product, implement, wherein, can transformation of energy type be only subject to the molecule in this stage with functionality and this conversion in the restriction of intrinsic non-compatibility of the condition that uses or reagent.Thereby the uncompatibility that this type of is intrinsic and carry out by the order with suitable the method that suitable conversion and synthesis step avoid their to occur and be easy to be understood by the those of ordinary skill in organic synthesis field by being.Below providing the example transforming, and should be understood that, described conversion is not only limited to for the group of the general genus of the conversion of illustration or substituting group.About other suitable conversion reference and be described in " guide is prepared by the comprehensive organic transformation-functional group of Comprehensive Organic Transformations-A Guide to Functional Group Preparations() ", R.C.Larock(La Luoke), VHC publishing company provides in (1989).The reference of other suitable reaction and be described in organic chemistry textbook, for example " Advanced Organic Chemistry(Advanced Organic Chemistry) " March(agate is strange), March, the 4th edition, McGraw Hill (1992) or " Organic Synthesis(organic synthesis) ", Smith(Smith), McGraw Hill, (1994)) in provide.Technology for purify intermediates and end product comprises, for example, the positive on post or on swivel plate and reverse-phase chromatography or, recrystallization, distillation and liquid-liquid or leaching, they will be easy to be understood by one skilled in the relevant art.Unless differently defined, the definition of substituting group and group is as in formula I.Term " room temperature " and " envrionment temperature " should refer to, unless otherwise indicated, and a temperature between 16 ℃ and 25 ℃.Term " backflow " should refer to, unless otherwise specified, and about a kind of solvent, at the boiling point of this solvent or the temperature on it.
Share the synthetic of intermediate 4
Synthesizing of two (trifluoromethyl) benzo thioamides (1) of 3,5-:
Figure BDA0000484103910001361
By two 3,5-(trifluoromethyl) cyanobenzenes (200g, 1.0eq) at DMF(1L) in a kind of solution pack in 3 neck round-bottomed flasks, add wherein NaSH(123.7g, 2.0eq.) and MgCl 2(186.7g, 1eq.).Be poured onto in ice-water slurry (10L) and with EtOAc(3x1L) this reaction mixture is stirred to 2-3h at ambient temperature before extracting.By salt solution for organic layer (3x100mL) washing of these merging, use anhydrous Na 2sO 4dry, filter and under reduced pressure concentrate to obtain 205g(90% productive rate) the thick thioamides of wanting (1), it is used in step subsequently like this.
3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazole (2) synthetic:
Figure BDA0000484103910001371
By two 3,5-(trifluoromethyl) benzo thioamides (1) (205.65g) at DMF(1.03L) in a kind of solution with water close hydrazine (73.16mL, 2.0eq.) and process.Before processing with formic acid (1.03L), this reaction mixture is stirred to 1h at ambient temperature.By this reaction mixture at 90 ℃ of backflow 2-3h, then allow it to be cooled to envrionment temperature, be poured onto in saturated water-based sodium bicarbonate (7L), and with EtOAc(3x1L) extract, by salt solution for organic layer (3x500mL) washing of these merging, use anhydrous Na 2sO 4dry, filter, and under reduced pressure concentrate, to obtain a kind of crude compound of 180g.By this for roughage sherwood oil (3x500mL) wash, filter and fully dry to obtain the triazole (2) of 160 grams (75% productive rates), obtain as a kind of light yellow solid.
(Z) synthesizing of-sec.-propyl 3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acrylate (3):
Figure BDA0000484103910001372
By 3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazole (2) (160g, 1.0eq.) is at DMF(960mL) in a kind of solution pack in 3 neck round-bottomed flasks.With DABCO(127.74g, 2eq.) process this solution and stirred 30min before processing with (Z)-sec.-propyl 3-iodo acrylate (150.32g, 1.1eq.).After 1hm, this reaction mixture is poured in frozen water slurry (5L) and with EtOAc(3x1L) extract.By salt solution for organic layer (3x100mL) washing of these merging, use anhydrous Na 2sO 4dry, filter, and under reduced pressure concentrate, to obtain a kind of crude compound of 250g.Carry out purifying by column chromatography (silica gel, with EtOAc/ hexane wash-out), obtain 138g(61% productive rate) pure isopropyl ester (3).
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4):
Figure BDA0000484103910001381
By (Z)-sec.-propyl 3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acrylate (3) (130g, 1.0eq.) at THF(1.3L) in a kind of solution pack in 3 neck round-bottomed flasks, and with LiOH(69.3g, 5eq) a kind of solution in water (1.3L) processes.With the dilution of 400mL water, with rare water-based HCl acidifying (pH=2-3) and with EtOAc(3x1L) extract before, this reaction mixture is stirred to 3-4h at ambient temperature.By the salt water washing of the organic layer of these merging, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate the productive rate with acquisition 110g(94%) compound (4) wanted; Z/E ratio=90.0/8.2(passes through LCMS).
(Z) synthesizing of-3-iodo vinylformic acid (1a):
Figure BDA0000484103910001382
A kind of sodium iodide (213.97g, 2.0eq) processing for solution by propynoic acid (50.0g, 1.0eq) in acetic acid (500mL).This reaction mixture is refluxed at 100 ℃ 2-3h, is then cooled to envrionment temperature, pours in frozen water (5.0L), neutralizes and use EtOAc(3x1L with saturated water-based sodium bicarbonate) extract.By salt solution for organic layer (3x1L) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate, to obtain the crude compound of 90.0g, (silica gel is used MeOH:CH to be passed through column chromatography 2cl 2wash-out) carry out purifying, obtain 56.0g(39.7% productive rate) pure carboxylic acid (1a).
Example 1
(Z) synthesizing of-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (2a):
Figure BDA0000484103910001391
By (Z)-3-iodo vinylformic acid (1a) (2.75g, 1.0eq.) at CH 2cl 2(25.0mL) a kind of solution in is cooled to 0 ℃, and uses successively DIPEA(1.96g, 1.1eq), HATU(5.78g, 1.1eq) and 3,3-difluoro azetidine hydrochloride (1.98g, 1.1eq) process.Before filtering and under reduced pressure concentrating, this reaction mixture is stirred to 2-3hr at 0 ℃, obtain the crude compound of 3.5g.Carry out purifying by column chromatography (silica gel, with EtOAc/ hexane wash-out), obtain the pure compound of wanting of 1.89g.Productive rate 49.87%.Quality: (ES+) 273.8 (M+1).
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001392
By 3-(3-(difluoromethyl)-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazole (2) (1.5g, 1.0eq.) at DMF(9.0mL) in a kind of solution DABCO(1.19g, 2.0eq.) process and using (Z)-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (2a) (1.60g, 1.1eq.) stirred 30min before processing.This reaction mixture is stirred to 2-3hr at ambient temperature, be then poured onto in frozen water slurry (90mL) and with EtOAc(3x50mL) extract.By salt solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate, to obtain a kind of crude amide of 2.0g.(cis-isomeride: 71.1%, trans-isomer(ide): 15.87%).Carry out purifying by column chromatography (silica gel, with EtOAC/ hexane wash-out), obtain the pure acid amides of wanting (22.0% productive rate) of 500mg:
1H?NMR(CDCl 3):δ9.63(s,1H),7.95-7.65(m,3H),7.24-7.27(d,J=10.8Hz,1H),5.66-5.69(d,J=10.8Hz,1H),4.46-4.59(m,4H)。C 16h 10f 8n 4the LCMS:[M+H of O] +be 427.27; Be found to be 427.29, RT:3.03min (98.17%).
(E)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (CDCl 3): δ 9.18 (s, 1H), 8.59 (s, 2H), 8.32 (s, 1H), (8.24-8.27 d, J=13.6Hz, 1H), (6.80-6.84 d, J=13.6Hz, 1H), 4.83-4.88 (m, 2H), 4.40-4.46 (m, 2H).C 16h 10f 8n 4the LCMS:[M+H of O] +be 427.27; Be found to be 427.34, RT:3.13min (100%).
(Z) substituting of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone is synthetic:
Figure BDA0000484103910001401
By (Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (33.0g, 1.0eq.) is at CH 2cl 2(660mL) a kind of solution in is cooled to 0 ℃, and uses successively HOBT(17.27g, 1.2eq), EDC.HCl(27.029g, 1.5eq) and 3,3-difluoro azetidine hydrochloride (14.61g, 1.2eq.) and DIPEA(24.31mL, 1.5eq) process.Carry out cancellation with 1L water and with EtOAc(3x500mL) this reaction mixture is stirred to 1.15hr at 0 ℃ before extracting.By the salt water washing of the organic layer of these merging, use anhydrous Na SO 4dry, and under reduced pressure concentrate, to obtain the crude compound of 35g.By column chromatography, (silica gel is used MeOH:CH 2cl 2wash-out) carry out purifying, obtain the pure acid amides of wanting (15g, 37% productive rate):
(Z)-3-(3-(3,5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (CDCl 3): δ 9.63 (s, 1H), 7.95-7.65 (m, 3H), 7.24-7.27 (d, J=10.8Hz, 1H), 5.66-5.69 (d, J=10.8Hz, 1H), 4.46-4.59 (m, 4H).C 16h 10f 8n 4the LCMS:[M+H of O] +be 427.27; Be found to be 427.29, RT:3.027 (98.17%).
Example 2
(Z) synthesizing of-3-(3-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (1):
Figure BDA0000484103910001412
By (Z)-sec.-propyl 3-(3-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylate (0.400g, 1.0eq.) at THF(5mL) and water (5mL) in a kind of solution LiOH(0.097g, 2.0eq.) process.This reaction mixture is at room temperature stirred to 2-3hr, with icy water (10mL) cancellation, is acidified to pH=1-2 with rare water-based HCl and also uses EtOAc(3x25mL) extraction.By the organic layer anhydrous Na of these merging 2sO 4dry, and under reduced pressure concentrate the productive rate with acquisition 150mg(42%) carboxylic acid wanted, it is used in step subsequently like this.Quality: (ES+) 302.19 (M+1).
(Z) synthesizing of-1-(3,3-difluoro azetidin-1-yl)-3-(3-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001421
By (Z)-3-(3-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (1) (0.150g, 1.0eq.) pack in a 25-mL flask, then at 0 ℃, use successively DIPEA(0.102mL, 1.2eq), EDC.HCl(0.143g, 1.5eq), 3,3-difluoro azetidine hydrochloride (0.077g, 1.2eq.) and HOBT(0.091g, 1.2eq), before processing, pack wherein methylene dichloride (3mL) into.This reaction mixture is stirred to 1hr at 0 ℃, water (5mL) dilution and extracting with methylene dichloride (3x5mL).Use Na 2sO 4dry, and under reduced pressure concentrate, the crude compound of 0.150g obtained.(cis 49%, trans 42%).By column chromatography, (silica gel is used MeOH/CH 2cl 2wash-out) carry out purifying, obtain the pure acid amides (0.025g wanting; 13% productive rate):
(Z)-1-(3,3-difluoro azetidin-1-yl)-3-(3-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 9.6 (s, 1H), 7.40-8.37 (m, 3H), 7.22-7.25 (d, J=10.8Hz, 1H), 5.64-5.67 (d, J=10.8Hz, 1H), 4.46-4.59 (m, 4H).C 15h 10f 6n 4the LCMS[M+H of O] +be 377.26; Be found to be 377.24 (at RT2.79min purity (92.79%)).Quality: (ES+) 377.2 (M+1).
Example 3
Figure BDA0000484103910001422
(Z) synthesizing of-3-(3-(3-hydroxyl-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (1):
Figure BDA0000484103910001431
By (Z)-sec.-propyl 3-(3-(3-hydroxyl-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylate (4g, 1.0eq.) at THF(40mL) and water (40mL) in a kind of solution LiOH(1.92g, 4eq.) process.This reaction mixture is at room temperature stirred to 2-3hr, then use (300mL) cancellation of acid ice-water slurry and with EtOAc(3x250mL) extract.By rare HCl solution (50mL) washing for the organic layer of these merging, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate, to obtain a kind of crude compound of 3g.By canescence compound thick gained like this for following steps.Output: 85.5%.Quality: (ES+) 299.92 (M+1).
(Z) synthesizing of-1-(3,3-difluoro azetidin-1-yl)-3-(3-(3-hydroxyl-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone (2):
Figure BDA0000484103910001432
By (Z)-3-(3-(3-hydroxyl-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (1) (1.5g, 1.0eq.) at 30ml CH 2cl 2in one cold (0 ℃) solution use successively DIPEA(0.78g, 1.2eq), EDC.HCl(01.15g, 1.2eq), 3,3-difluoro azetidine hydrochloride (0.78g, 1.2eq.) and HOBt(0.92g, 1.2eq) process.Before under reduced pressure concentrating, this reaction mixture is stirred to 3-4hr at 0 ℃, obtain the crude compound of 0.5g.(during reaction not observing trans-isomer(ide)).This crude reaction mixture is carried out to purifying by column chromatography, obtain the pure acid amides of wanting (0.5g).Output: 26.7%.
(Z)-1-(3,3-difluoro azetidin-1-yl)-3-(3-(3-hydroxyl-5-(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 10.53 (1H, D 2o is tradable), 9.17 (s, 1H), 7.14-7.71 (m, 3H), 7.41-7.43 (d, J=10.4Hz, 1H), 5.92-5.95 (d, J=10.4Hz, 1H), 4.41-4.49 (m, 4H) .C 15h 11f 5n 4o 2lCMS[M+H] +be 375.27; Be found to be 375.24 (at RT2.44min purity (97.03%)).Quality: (ES+) 375.2 (M+1).
Example 5
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro piperidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001441
By (Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (1.0g, 1.0eq.) is at CH 2cl 2(20mL) one cold (0 ℃) solution in is used EDC.HCl(0.656g, 1.2eq successively), 3,3-difluoro piperidine hydrochlorate (0.540g, 1.2), DIPEA(435mg, 1.2eq) and HOBT(25.92g, 1.2eq.) process.This limpid reaction mixture is stirred to 1.5-2h at 0 ℃, then carry out cancellation and use CH with 50mL ice-water slurry 2cl 2(2x25mL) extract.By the salt water washing of the organic layer of these merging, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate, to obtain the crude compound of 0.70g.As by LCMS and 1h NMR confirms, does not form trans-compound.Carry out purifying by column chromatography, obtain 0.20g material, use ether: this material of sherwood oil further by recrystallize/grindings to remove aliphatic impurity, acquisition 0.180g(14.1% productive rate) the pure compound of wanting.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro piperidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 8.739 (s, 1H), 7.94-8.59 (m, 3H), 7.13-7.15 (d, J=10.4Hz, 1H), 5.99-6.016 (d, J=10.4Hz, 1H), 3.95-4.01 (t, 1H), 3.68-3.77 (m, 2H), 3.56-3.53 (t, 1H), 2.11-2.05 (m, 2H), 1.77-1.89 (m, 2H).C 18h 14f 8n 4the LCMS[M+H of O] +be 455.33; Be found to be 455.07 (at RT3.82min, purity (98.64%)).
Example 6
Figure BDA0000484103910001451
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(4,4-difluoro piperidin-1-yl) third-2-alkene-1-ketone:
By (Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (0.500g, 1.0eq.) is at CH 2cl 2(20mL) one cold (0 ℃) solution in is used EDC.HCl(0.409g, 1.5eq successively), 4,4-difluoro piperidine hydrochlorate (0.269g, 1.2), DIPEA(0.220g, 1.2eq) and HOBT(0.261g, 1.2eq.) process.This limpid reaction mixture is stirred to 1.5-2h at 0 ℃, then carry out cancellation with 50mL ice-water slurry.By this water layer CH 2cl 2(2x25mL) extract, and by the salt water washing of the organic layer of these merging, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate, to obtain the crude compound of 0.60g.By preparative TLC(MeOH/CH 2cl 2wash-out) carry out purifying, obtain 0.090g compound, it is further used to ether: sherwood oil grinds to remove aliphatic impurity, obtain the pure compound of 0.06g.Output: 9.28%.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(4,4-difluoro piperidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 8.705 (s, 1H), 8.557 (s, 2H), 7.950 (s, 1H), 7.111-7.136 (d, J=10.0Hz, 1H), 5.998-6.024 (d, J=10.8Hz, 1H), 3.886-3.916 (t, 2H), (3.654-3.683 t, 2H), 2.055-2.152 (m, 2H), 1.940-2.035 (m, 2H).C18H15F8N4O[M+H]+LCMS be 455.33; Be found to be 455.38 (at RT3.057min purity (99.77%).
Example 7
Figure BDA0000484103910001461
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-fluorine azetidin-1-yl) third-2-alkene-1-ketone:
At 0 ℃, to (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (0.500g, 1eq.), methylene dichloride (10mL, 20V) in the solution of a kind of stirring in the 3 neck 100mL round-bottomed flasks that are equipped with nitrogen bubble device, add HOBT(0.19g, 1.2eq), EDC.HCl(0.41g, 1.5eq) and DIPEA(0.27g, 1.5eq) process.After 1hr, this reaction mixture water (50ml) is carried out to cancellation and extract with methylene dichloride (3x30mL).By salt solution for organic layer (50mL) washing of these merging, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate, the rough title compound of 0.25g obtained.Carry out purifying by flash chromatography (with EtOAc/ hexane wash-out), obtain the pure title compound of 0.03g.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-fluorine azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 9.76 (s, 1H), 8.62 (s, 2H), 7.94 (s, 1H), 7.21-7.24 (d, J=10.8Hz, 1H), 5.65-5.68 (d, J=10.8Hz, 1H), 5.45-5.48 (m, 1H), 5.31-5.34 (m, 1H), 4.44-4.56 (m, 4H), 4.23-4.43 (m, 2H).C16H11F7N4O[M+H]+LCMS be 409.28; Be found to be 409.38 (at RT2.963min purity (96.03%).
Example 8
Figure BDA0000484103910001471
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy-3-methyl azetidin-1-yl) third-2-alkene-1-ketone:
In a 25mL3N round-bottomed flask that disposes nitrogen entrance, pack (Z)-3-(3-(3 into, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (0.250g, 1.0eq.) together with methylene dichloride (5.0mL, 20V).This reaction mixture is cooled to 0 ℃, and then adds HOBT(0.119g, 1.1eq.), then add EDCHCl(0.149g, 1.1eq.) and 3-methyl azetidin-3-alcohol HCl(0.096g, 1.1eq.).At the same temperature, in this reaction mixture, dropwise add DIPEA(0.101g, 1.1eq).This limpid reaction mixture is stirred to 1.5h at 0 ℃.By silica gel tlc analysis (use in methylene dichloride 10% methyl alcohol as moving phase) and by the visual progress of following the trail of this reaction of UV.Reaction mixture is carried out in 20mL ice-water slurry to cancellation.Separate organic layer, and water layer is extracted to guarantee to extract completely with methylene dichloride (2x10mL).This organic layer is washed with salt brine solution, and use anhydrous Na 2sO 4dry, and concentrate by rotary evaporation under decompression (35,20mm Hg), to obtain the crude compound of 0.280g.(cis: 61.9%, trans: 16.46%).
This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 0.2%-2.0% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 90mg.Productive rate: 30.1%.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy-3-methyl azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, DMSO) δ 9.39 (s, 1H), 8.55 (s, 2H), 8.301 (s, 1H), 7.37-7.40 (d, J=10.4Hz, 1H), 5.95-5.98 (d, J=10.0Hz, 1H), 5.69 (s, 1H), 3.90 (s, 2H), 3.78-3.85 (m, 2H), 1.32 (s, 3H).C 17h 14f 6n 4o 2lCMS[M+H] +be 420.31; Be found to be 421.4 (at RT2.665min purity (99.54%)).
Example 9
4-(4,4,5,5-tetramethyl--1,3,2-bis-Evil ring pentaborane-2-yl)-2, two (trifluoromethyl) pyridines (1) of 6-synthetic:
Figure BDA0000484103910001482
In a 10mL sealed tube, at N 2under atmosphere, by (0.146g, 0.5eq.), DTBPY(0.0015g, 0.005eq.) and [Ir (OMe) (COD)] 2(0.0019g, 0.0025eq.) be dissolved in 5mL Ganji alkane.By this reaction mixture at stirring at room temperature 10min, to provide dark red solution.Pack two 3,5-(trifluoromethyl) pyridines (0.250g, 1eq.) into sealed tube.Closing seam pipe at 50 heating 6h.Use ethyl acetate using TLC(: hexane (1:9) is as moving phase) the completing of monitoring reaction.By this reaction mixture at ice-water slurry (50mL)) in carry out cancellation and extract in ethyl acetate (3x50mL).With salt brine solution (3x50mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filters, and under reduced pressure concentrate to provide 0.40g rough title compound.This roughage is directly used in next step and without purifying.
Synthesizing of two (trifluoromethyl)-4-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-1,2, the 4-triazole-3-yl) pyridines (2) of 2,6-:
In a 10mL sealed tube, by 4-(4,4,5,5-tetramethyl--1,3,2-bis-Evil ring pentaborane-2-yl)-2, two (trifluoromethyl) pyridine (the 1) (0.395g of 6-, 1eq.) be dissolved in DMF(5mL) in, be then added on the bromo-1-of 3-((2-(trimethyl silyl) oxyethyl group) the methyl)-1H-1 in water (1mL), 2,4-triazole (0.323g, 1eq.) and K 2cO 3(0.480g, 3eq.).Mixture is carried out to degasification by purging nitrogen 1h.By Tetrakis(0.067g, 0.05eq.) be added in this reaction mixture and by sealed tube at 90 ℃ underheating 18h.Use ethyl acetate using TLC(: hexane (2:8) is as moving phase) the completing of monitoring reaction.By this reaction mixture at ice-aqueous solution (50mL)) in carry out cancellation and extract in ethyl acetate (3x50mL).With salt brine solution (3x50mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filters, and under reduced pressure concentrate to provide 0.30g crude compound.By column chromatography (using ethyl acetate/n-hexane as moving phase), this compound is carried out to purifying.Locate compound in 8% ethyl acetate (in hexane) and eluted, obtain (intermediate-2) 0.150g.Output: 31.0%.
4-(1H-1,2,4-triazole-3-yl)-2, two (trifluoromethyl) pyridines (3) of 6-synthetic:
Figure BDA0000484103910001501
In a 10mL sealed tube, by 2, two (trifluoromethyl)-4-(1-((2-(trimethyl silyl) oxyethyl group) the methyl)-1H-1 of 6-, 2,4-triazole-3-yl) pyridine (2) (0.15g, 1eq.) is dissolved in diox HCl(5mL) in and sealed tube be heated to 60 continue 6h.Use ethyl acetate using TLC(: hexane (5:5) is as moving phase) the completing of monitoring reaction.By this reaction mixture at ice-water NaHCO 3solution (50mL)) in carry out cancellation and extract in ethyl acetate (3x50mL).With salt brine solution (3x50mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filters, and under reduced pressure concentrate to provide 0.3g crude compound.By column chromatography (using ethyl acetate/hexane as moving phase), this compound is carried out to purifying.Locate compound in 30% ethyl acetate (in hexane) and eluted, obtain 4-(1H-1,2,4-triazole-3-yl)-2, two (trifluoromethyl) pyridine (3) 0.060g of 6-.Output: 58.4%.
(Z) synthesizing of-3-(3-(two (trifluoromethyl) pyridin-4-yls of 2,6-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001502
In 3 neck 50mL round-bottomed flasks, by 4-(1H-1,2,4-triazole-3-yl)-2, two (trifluoromethyl) pyridine (the 3) (0.060g of 6-, 1eq.) be dissolved in DMF(2mL with (Z)-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (0.064g, 1.1eq.)) in.At room temperature add DABCO(0.047g, 2eq.).Reaction mixture is at room temperature stirred to 1h.Use MeOH: methylene dichloride (0.25:9.75) is monitored and reacted on TLC as moving phase.By this reaction mixture at ice-water slurry (50mL)) in carry out cancellation and extract by ethyl acetate (3x25mL).With salt brine solution (3x25mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filter, and under reduced pressure concentrating provides 0.70g crude compound, passed through preparative TLC(and used 2.5% methyl alcohol in methylene dichloride as moving phase) carry out purifying, obtain 0.011g(12%) title compound.
(Z)-3-(3-(two (trifluoromethyl) pyridin-4-yls of 2,6-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, DMSO) δ 9.768 (s, 1H), 8.590 (s, 2H), 7.268-7.295 (d, J=10.8,1H), 5.732-5.759 (d, J=10.8Hz, 1H), 4.56-4.62 (t, 2H), 4.46-4.52 (t, 2H).The LCMS[M+H of C15H9F8N5O]+be 427.25; Be found to be 428.5 (at 2.901min purity (95.46%)).
Example 10
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-) 1H-1,2,4-triazol-1-yl)-N-ethyl-N-(1-(pyridin-3-yl) ethyl) acrylamide:
Figure BDA0000484103910001511
At 0 ℃ at N 2in atmosphere, in 3 neck 50mL neck round-bottomed flasks, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) is dissolved in methylene dichloride (15mL).In this reaction, add DIPEA(0.088g, 1.2eq.), EDC HCl(0.131g, 1.2eq.) and N-ethyl-1-(pyridin-3-yl) ethamine (0.102g, 1.2eq.), then add HOBT(0.104g, 1.2eq.).Reaction mixture is stirred to 1h at 20 ℃.The progress of reaction is followed the tracks of by silica gel tlc analysis, uses 10% methyl alcohol: methylene dichloride is as moving phase visual with UV, SM Rf=0.15 and product Rf=0.40.Reaction is stirred to 3-4h and under reduced pressure utilized rotary evaporation to evaporate to provide 0.4g crude compound in yellow reaction mixture.
Use silica gel 60/120 to use methyl alcohol this crude reaction mixture: methylene dichloride carries out purifying as moving phase by column chromatography.By this post (2x10cm) filling methylene dichloride, and start wash-out in gradient mode with methyl alcohol, since 1.5% to 2.5% methyl alcohol (in methylene dichloride) fraction collection (25mL part)).Compound starts wash-out with 1.5% methyl alcohol (in methylene dichloride).The part that comprises this kind of TLC profile is collected together to obtain pure compound (0.006g).Output: 3%.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-) 1H-1,2,4-triazol-1-yl)-N-ethyl-N-(1-(pyridin-3-yl) ethyl) acrylamide: 1h NMR (400MHz, DMSO) δ 9.04 (s, 1H), 7.38-8.73 (m, 7H), 8.19-8.22 (d, J=12.4,1H), 6.01-6.04 (d, J=12.8Hz, 1H), 4.77-4.79 (d, 1H), 3.29-3.46 (m, 2H), 1.79-1.81 (d, 3H), 1.24-1.27 (t, 3H).C 22h 19f 6n 5the LCMS[M+H of O] +be 483.4; Be found to be 484.55 (at 3.283min purity (91.38%)).
Example 11
Figure BDA0000484103910001521
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-N-(oxazole-5-ylmethyl) acrylamide synthetic: in a 25mL3 neck round-bottomed flask that disposes nitrogen entrance, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (0.250g, 1.0eq.) be dissolved in methylene dichloride (5.0mL, 20V).This reaction mixture is cooled to 0, and then adds HOBT(0.119g, 1.1eq.), then add EDCHCl(0.150g, 1.1eq.) with oxazole-5-base methylamine HCl(0.143g, 1.1eq.).At the same temperature, in this reaction mixture, dropwise add DIPEA(0.101g, 1.1eq).This limpid reaction mixture is stirred to 1.5h at 0 ℃.By silica gel tlc analysis (use 5% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of following the trail of this reaction of UV.
By reaction mixture cancellation in ice-water slurry (20mL).Separate organic layer, and water layer is extracted to guarantee to extract completely with methylene dichloride (2x10mL).This organic layer is washed with salt brine solution, and use anhydrous Na 2sO 4dry, and concentrate by rotary evaporation under decompression (35,20mm Hg), to obtain the crude compound (cis: 30.71% of 0.280g; Trans: 28.02%).
This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from the 0.2%--2.0% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile (TLC profile) is collected together to obtain 90mg compound cis and trans mixture.(cis: 57.86%, trans: 52.49%).
Use 5% methyl alcohol by preparative TLC(: methylene dichloride is as moving phase) this mixture is carried out to purifying.The part that comprises this kind of TLC profile is collected together to obtain to the compound of 15mg, pure compound.(4.88% productive rate).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(oxazole-5-ylmethyl) acrylamide: 1h NMR (400MHz, DMSO) δ 9.62 (s, 1H), 9.05 (s, 1H), 8.53 (s, 2H), 8.30 (s, 2H), 7.41-7.44 (d, J=10.4Hz, 1H), 7.07 (s, 1H), 5.95-5.98 (d, J=10.8Hz, 1H), 4.47-4.48 (d, 2H).C 17h 11f 6n 5o 2lCMS[M+H] +be 431.28; Be found to be 432.39 (at RT2.822min purity (95.52%)).
Example 12
(Z) synthesizing of-3-(5-(two (trifluoromethyl) phenyl of 3,5-)-4H-1,2,4-triazole-3-yl) vinylformic acid (2):
In 3 neck 100mL round-bottomed flasks, two 3,5-(trifluoromethyl) benzo thioamides (0.564g, 1eq.) are dissolved in to DMF(5mL, 10V) in, hydrazine hydrate (0.123g, 1.2eq.) then at 0 ℃, added.This reaction mixture is at room temperature stirred until SM consumes and be converted into the hydrazine adducts of polarity.Preserve from the sample of this reactive material and be used for TLC.Finally at 0 ℃, add maleic anhydride (0.242g mL, 1.2eq.).Then reaction mixture is at room temperature stirred until all hydrazine adductss consumption be converted into acyclic intermediate.Again preserve this acyclic intermediate sample for TLC.Reaction mixture is heated to 6h at 80 ℃.Use MeOH: methylene dichloride (2:8) is monitored and reacted as SM as moving phase and acyclic intermediate on TLC.By this reaction mixture at ice-aqueous solution (100mL)) in carry out cancellation and extract by ethyl acetate (3x50mL).With salt brine solution (3x50mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filters, and under reduced pressure concentrate to provide 0.51g crude compound.This crude compound is dissolved in the diethyl ether of minimum quantity.This solution is stirred and precipitates compound at-5 times, filter and use the diethyl ether of refrigeration to wash to provide 0.150g(20%) pure (Z)-3-(5-(3, two (trifluoromethyl) phenyl of 5-)-4H-1,2,4-triazole-3-yl) vinylformic acid.
(Z) synthesizing of-3-(5-(two (trifluoromethyl) phenyl of 3,5-)-4H-1,2,4-triazole-3-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001551
In 3 neck 50mL round-bottomed flasks, by (Z)-3-(5-(3, two (trifluoromethyl) phenyl of 5-)-4H-1,2,4-triazole-3-yl) vinylformic acid (2) (0.065g, 1.0eq.), 3,3-difluoro azetidine HCl(0.028g, 1.2eq.) and EDC.HCl (0.042g, 1.2eq.) be dissolved in methylene dichloride (5mL).Add DIPEA(0.028g, 1.2eq at-5 times), then at the same temperature, add HOBt(0.033g, 1.2eq.).Reaction is remained on to this temperature 1h.Use MeOH: methylene dichloride (0.5:9.5) is monitored and reacted on TLC as moving phase.By this reaction mixture at ice-water slurry (50mL)) in carry out cancellation and extract by ethyl acetate (3x20mL).With salt brine solution (3x25mL) washing organic layer.Organic layer is dried by anhydrous sodium sulphate, filters, and under reduced pressure concentrate to provide 0.80g crude compound, by column chromatography (using ethyl acetate and hexane as moving phase), this crude compound is carried out to purifying.With 35% ethyl acetate (in hexane), product is carried out to wash-out to provide 0.055g(78%) title compound.
(Z)-3-(5-(two (trifluoromethyl) phenyl of 3,5-)-4H-1,2,4-triazole-3-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, DMSO) δ 14.826 (s, 1H, D 2o is tradable), 8.557 (s, 2H), 8.259 (s, 1H), 6.847-6.877 (d, J=12,1H), 6.445-6.476 (d, J=12.4Hz, 1H), 4.611 (m, 2H), 4.480 (m, 2H).C 16h 10f 8n 4the LCMS[M+H of O] +be 426.26; Be found to be 427.3 (at 3.303min purity (99.83%)).
Example 13
Figure BDA0000484103910001561
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-N-((2-methylpyrimidine-5-yl) methyl) acrylamide synthetic: in a 25mL3 neck round-bottomed flask that disposes nitrogen entrance, pack (Z)-3-(3-(3 into, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (0.1g, 1.0eq.) together with methylene dichloride (5.0mL, 50V) and ethyl acetate (5.0mL, 50V).This reaction mixture is cooled to 0 ℃, and then adds T3P(50% in ethyl acetate) (0.214g, 1.2eq.), then add DIPEA(0.073g, 2.0eq.) and (2-methylpyrimidine-5-yl) methylamine (0.038g, 1.1eq.).This limpid reaction mixture is stirred to 30min at 0 ℃.By silica gel tlc analysis (use 10% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of following the trail of this reaction of UV.Reaction mixture is carried out in 30mL ice-water slurry to cancellation.Separate organic layer, and water layer is extracted to guarantee to extract completely with methylene dichloride (2x20mL).This organic layer is washed with salt brine solution, and use anhydrous Na 2sO 4dry, and concentrate by rotary evaporation under decompression (35,20mm Hg), to obtain the crude compound of 0.129g.(cis: 81.98%; Trans: not detect; Unreacted SM:13.95%).
This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 0.2% to 4.0% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain to the pure compound of 65mg.Output: 50.38%.
(Z)-3-(3-(two (the trifluoromethyl)-1H-1 of 3,5-, 2,4-triazol-1-yl)-N-(2-methylpyrimidine-5-yl) acrylamide: 1h NMR (400MHz, DMSO) δ 9.57 (s, 1H), (9.12 s, 1H), 8.62 (s, 2H), 8.55 (s, 2H), (7.41-7.43 d, J=10.4Hz, 1H), (5.98-6.01 d, J=10.4Hz, 1H), 4.38-4.39 (d, 2H).C 19h 14f 6n 6the LCMS[M+H of O] +be 456.34; Be found to be 457.39 (at RT2.725min purity (99.81%)).
Example 14
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(pyrimidine-5-ylmethyl) acrylamide:
In a 50mL3 neck round-bottomed flask that disposes nitrogen entrance, pack (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1 into, 2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) is together with methylene dichloride (5mL, 10V).This reaction mixture is cooled to-20, and then in this reaction mixture, adds pyrimidine-5-base methylamine (0.075g, 1.2eq.), T3P(50% in EtOAc) (0.4mL, 1.2eq), then dropwise add DIPEA(0.2mL, 2eq.).This reaction mixture is stirred at-20 ℃ to another 30min.By silica gel tlc analysis (use 5% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of following the trail of this reaction of UV.Reaction mixture is concentrated to obtain crude compound by rotary evaporation (25,20mm Hg).This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 4% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.2g.Productive rate: 80%.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(pyrimidine-5-yl) methyl) acrylamide: 1h NMR (400MHz, DMSO) δ=9.58 (s, 1H), 9.07 (s, 2H), 8.76 (s, 2H), 8.50 (s, 2H), 8.28 (s, 1H), (7.44-7.41 d, J=10.4Hz, 1H), (6.02-5.99 d, J=10.4Hz, 1H), (4.45-4.43 d, J=5.6Hz, 2H).LCMS(%)：100%。
Example 15
Figure BDA0000484103910001581
Synthesizing of 6-bromo methyl cycloheptapyridine formaldehyde (1a):
Figure BDA0000484103910001582
By THF(30mL) pack in three neck 100mL round-bottomed flasks that have magnetic agitation, a kind of immerseable thermometer and an a kind of feed hopper and be cooled to-78.N-butyllithium (1.35g, 21.10mmol) is carefully added in this reaction, keep-70 internal temperature.adding 2,6-dibromo pyridine (5.0g, 21.10mmol) afterwards, the dark green solution of gained is being stirred to 15min, then adding pure DMF(2.31g, 31.66mmol through the time period of 30 seconds).At-70 ℃, this reactive material is stirred to 15min.Monitor the progress of this reaction by silica gel tlc analysis (using ethyl acetate: hexane (3:7) is as moving phase).Reaction mixture is poured over to saturated NH 4cl(50mL) in and with EtOAc(3x50mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate by rotary evaporation, to obtain the crude compound of 5.0g, it is carried out to purifying by chromatography.With 3% ethyl acetate (in hexane), product is carried out to wash-out to provide 1.5g pure products (productive rate 38.4%).
Synthesizing of 6-(two (trifluoromethyl) phenyl of 3,5-) picoline formaldehyde:
Figure BDA0000484103910001591
In a 35mL microwave bottle, at room temperature, will be dissolved in 3 in 1,2-glycol dimethyl ether (20mL), two (trifluoromethyl) phenyl-boron dihydroxides (2.0g, 7.7mmol) of 5-and 6-bromo methyl cycloheptapyridine formaldehyde (1a) (1.44g, 7.7mmol) are used K 2cO 3(3.22g, 23.3mmol) a kind of solution in water is processed.In reactive material, add Pd (dppf) Cl 2. methylene dichloride and at 90 ℃, pack microwave in continue 30min.Monitor the progress of this reaction by silica gel tlc analysis (using ethyl acetate: hexane (3:7) is as moving phase).Reaction mixture is poured in water (50mL) and with EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate by rotary evaporation, to obtain the crude compound of 2.5g, it is carried out to purifying by chromatography.In 4% ethyl acetate (in hexane) from product wash-out to provide 1.2g pure products.(productive rate 48.38%).
(E)-3-(6-(two (trifluoromethyl) phenyl of 3,5-) pyridine-2-yl) is acrylic acid synthetic:
Figure BDA0000484103910001592
In a 35mL microwave bottle, 6-(two (trifluoromethyl) phenyl of 3,5-) picoline formaldehyde (1) (0.3g, 0.93mmol) and propanedioic acid (0.097g, 0.93mmol) are dissolved in ethanol.Piperidines (2-3 drips) is added in reaction and in microwave, at 90 ℃, to continue 20min.Follow the trail of the progress of this reaction by silica gel tlc analysis (using 10%MeOH-methylene dichloride as moving phase).Reaction mixture is poured in water (15mL) and with EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and concentrate by rotary evaporation, to obtain the crude compound of 0.4g, use it for next step and be not further purified.
(E) synthesizing of-3-(6-(two (trifluoromethyl) phenyl of 3,5-) pyridine-2-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001601
In a 50-mL round-bottomed flask, by intermediate 2(0.4g, 1.1mmol) and 3,3-difluoro azetidine hydrochloride (0,17g, 1.3mmol) be dissolved in methylene dichloride (20mL).At room temperature add propyl phosphonous acid acid anhydride (0.42g, 1.3mmol), DIPEA(0.28g, 2.2mmol) and reaction mixture is stirred to 30min.Also by the visual progress of following the trail of this reaction of UV, by reaction mixture cancellation in frozen water slurry, filter it by silica gel tlc analysis (using 0.5% methyl alcohol: methylene dichloride is as moving phase), compound is extracted in methylene dichloride, use Na 2sO 4dry, filter, and concentrate by rotary evaporation (28,20mm Hg), to obtain the rough thing of a kind of solid of 0.5g, by flash chromatography carry out purifying and with at absolute dichloromethane place product wash-out to obtain 0.030g output (6.2%).
(E)-3-(6-(two (trifluoromethyl) phenyl of 3,5-) pyridine-2-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 8.55 (S, 2H), 7.97 (s, 1H), 7.89-7.93 (t, 1H), 7.81-7.83 (d, 2H), (7.75-7.79 d, J=15.2,1H), (7.45-7.47 d, 1H), 7.18-7.22 (d, J=15.2,1H), 4.68-4.70 (t, 2H), 4.50-4.53 (t, 2H) C 19h 12f 8n 2the LCMS[M+H of O] +be 436.3; Be found to be 437.39 (at RT3.34min purity (93.47%)).
Example 16
Figure BDA0000484103910001611
Synthesizing of 4-(two (trifluoromethyl) phenyl of 3,5-)-1H-imidazoles (1):
Figure BDA0000484103910001612
In a 35mL microwave bottle, two 3,5-(trifluoromethyl) phenyl-boron dihydroxides (1) (2.5g, 9.69mmol) and the iodo-1H-imidazoles of 4-(2.068g, 10.66mmol) are dissolved in Isosorbide-5-Nitrae-dioxs (18mL).At room temperature, in this reaction mixture, add NaHCO 3the aqueous solution (1.628g, 19.38mmol).By degassed this compound of reaction 30min and by Pd (dppf) Cl 2methylene dichloride (0.791g, 0.1eq.) packs in microwave and at 90 ℃, to continue 16h.Use methyl alcohol by TLC(: methylene dichloride (0.5:9.5) is as moving phase) monitor the progress of this reaction.Reaction mixture is poured in water (50mL) and is filtered by bed of diatomaceous earth.By this filtrate EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate by rotatory evaporator, to obtain the crude compound of 2.5g, it is carried out to purifying by column chromatography.40% ethyl acetate (in hexane) locate compound by wash-out to provide 0.640g pure products (productive rate 23.61%).Repeat same batch to provide 0.781g pure products (productive rate 28.78%) with the chemical of same amount.
(Z) synthesizing of-sec.-propyl 3-(4-(two (trifluoromethyl) phenyl of 3,5-)-1H-imidazoles-1-yl) acrylate (2):
Figure BDA0000484103910001621
In a 100mL3N round-bottomed flask that disposes nitrogen entrance, temperature meter base and stopper, by 4-(3, two (trifluoromethyl) phenyl of 5-)-1H-imidazoles (1) (1.1g, 1.0eq.) be dissolved in methylene dichloride (20mL, 19V), this reaction mixture is cooled to 0.In this reaction mixture, add TEA(0.709mL, 1.3eq. at 0 time), then add isopropyl acrylate (0.571g, 1.3eq.) and this reaction mixture is stirred to 30min.Follow the trail of the progress of this reaction by silica gel tlc analysis (using 20% ethyl acetate-n-hexane as moving phase).Reaction mixture is poured in water (50mL).By this filtrate EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and concentrate by rotary evaporation, to obtain the crude compound of 1.2g, it is carried out to purifying by column chromatography.Locate product wash-out to provide 1.0g crude product (cis 39%+ trans 56%) (productive rate 65.35%) in 4% ethyl acetate (in hexane).
(Z) synthesizing of-3-(4-(two (trifluoromethyl) phenyl of 3,5-)-1H-imidazoles-1-yl) vinylformic acid (3):
Figure BDA0000484103910001631
In a 50mL3 neck round-bottomed flask that disposes nitrogen entrance, temperature meter base and stopper, by (Z)-sec.-propyl 3-(4-(3, two (trifluoromethyl) phenyl of 5-)-1H-imidazoles-1-yl) acrylate (2) (1.0g, 1.0eq.) is dissolved in THF:H 2o(20mL, 1:1,20V) in.At 0 ℃, in this reaction mixture, add LiOH.H2O(0.535g, 5.0eq.).This reaction mixture is stirred to 3-4h and uses 20% ethyl acetate/n-hexane as moving phase using TLC() monitor the progress of this reaction.Reaction mixture is used to rare HCl acidifying.By this reaction mixture EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate by rotary evaporation, to obtain the crude compound of 0.4g, use it for next step and do not carry out purifying.
(Z) synthesizing of-3-(4-(two (trifluoromethyl) phenyl of 3,5-)-1H-imidazoles-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910001632
In a 50mL3 neck round-bottomed flask that disposes nitrogen entrance, temperature meter base, stopper, by (Z)-3-(4-(3, two (trifluoromethyl) phenyl of 5-)-1H-imidazoles-1-yl) vinylformic acid (3) (0.4g, 1.0eq.) be dissolved in methylene dichloride (8mL, 20V), this reaction mixture is cooled to 0 ℃.At 0 ℃, in this reaction mixture, add HOBT(0.209g, 1.2eq.), difluoro azetidine HCl(0.177g, 1.2eq.) and EDC.HCl(0.328g, 1.5eq.).At 0 ℃, in this reaction mixture, dropwise add DIPEA(0.177g, 1.2eq.).Use 5% methyl alcohol-methylene dichloride to follow the trail of the progress of this reaction by TLC as moving phase.Reaction mixture is toppled over and is entered in water (50mL) and by compound EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of this merging, use MgSO 4dry, filter, and concentrate by rotary evaporation, to obtain the crude compound of 0.420g, it is carried out to purifying by column chromatography.0.5%-0.6% methyl alcohol (in methylene dichloride) locate compound by wash-out to provide 0.05g pure products (productive rate 10.41%).
(Z)-3-(4-(two (trifluoromethyl) phenyl of 3,5-)-1H-imidazoles-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 8.57 (s, 1H), 8.27 (s, 2H), 8.06 (s, 1H), 7.78 (s, 1H), 6.94-6.91 (d, J=12,1H), 5.47-5.45 (d, J=8,1H), 4.58-4.45 (m, 4H).C 17h 11f 8n 3the LCMS[M+H of O] +be found to be 281.34 (at RT2.54min purity (99.13%)).
Example 17
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-(pyrimidine-5-ylmethyl) acrylamide:
Figure BDA0000484103910001641
In a 50mL3N round-bottomed flask that disposes nitrogen entrance, pack (Z)-3-(3-(3 into, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-N-(pyrimidine-5-ylmethyl) acrylamide (0.05g, 1.0eq.) together with THF(5mL, 5V).This reaction mixture is cooled to-20 ℃ and interpolation sodium hydride (60% in mineral oil) (0.051g, 1.1eq.).Allow reaction mixture to stir 1h.In this reaction mixture, add methyl-iodide (0.018g, 1.1) and stir 1h at-20 ℃.By silica gel tlc analysis (use 5% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of following the trail of this reaction of UV.By reaction mixture in water (50mL) cancellation and with EtOAc(50 × 2) extract.This organic layer is washed with salt brine solution, and use Na 2sO 4dry, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain the crude compound of 0.060g.This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 4% methyl alcohol in methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.015g productive rate (30%).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-(pyrimidine-5-ylmethyl) acrylamide: 1h NMR (400MHz, DMSO) δ=9.04-8.99 (d, J=21.6Hz, 2H), 8.77-8.71 (d, J=24Hz, 2H), 8.46 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.42-7.38 (m, 1H), 6.37-6.35,6.31-6.28 (d, J=10Hz, J=10.4Hz, 1H), 4.68-4.61 (d, J=28Hz, 2H), 2.99-2.96 (d, J=14Hz, 3H).C 19h 14f 6n 6the LCMS[M+H of O] +be 456.3; Be found to be 457.44 (at RT2.59min purity (94.12%)).If the compound of observing confirming by NMR is rotational isomer.
Example 18
Figure BDA0000484103910001651
Synthesizing of N-methyl isophthalic acid-(2-methylpyrimidine-5-yl) methylamine (1):
In three neck 100mL round-bottomed flasks that are equipped with magnetic agitation, immerseable thermometer and nitrogen bubble device, be enclosed in the 5-pyrimidine formaldehyde-2-methyl (1g, 0.0082mol.) in methyl alcohol (10mL) and be cooled to 0 ℃.Methylamine (20.5mL, 0.0409mol.) and acetic acid (2.4mL, 0.0409mol.) are added in this reaction, keep 0 ℃.The deep yellow solution of gained is stirred to 2h.Time period through 10min is added sodium cyanoborohydride (2.05g, 0.0328mol.).This reactive material is at room temperature stirred to 2-3h.By silica gel tlc analysis (use methyl alcohol: methylene dichloride (0.5:9.5) is together with TEA(1%) as moving phase) follow the trail of the progress of this reaction.It shows that parent material exhausts after at room temperature stirring 3hr.Under reduced pressure remove solvent, by shrend go out and with EtOAc(3x50mL) extract.By salt brine solution for organic layer (3x15mL) washing of these merging, by dried over sodium sulfate, filter, and concentrate by rotary evaporation, to obtain the crude compound of 0.5g.This roughage is stood to column purification, use silicon 60/120 as stationary phase and methylene dichloride: methyl alcohol is as moving phase.By this post filling methylene dichloride, and start wash-out in gradient mode with methyl alcohol, start the methyl alcohol (the methylene dichloride with 1%TEA) to 3.0%, fraction collection from 0.5.0%.Compound starts wash-out with 2.5% methyl alcohol (in the methylene dichloride with 1%TEA).The part that comprises this kind of TLC profile is collected together to obtain to the pure products of compound 200mg.(productive rate 17.78%).
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-((2-methylpyrimidine-5-yl) methyl) acrylamide:
Figure BDA0000484103910001671
In a 25mL3 neck round-bottomed flask that disposes nitrogen entrance, pack N-methyl isophthalic acid-(2-methylpyrimidine-5-yl) methylamine (1) (0.1g into, 1.0eq.) with (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.178g, 0.7eq.) is together with methylene dichloride (2mL, 10V).This reaction mixture is cooled to-20 ℃, and then in this reaction mixture, adds T3P(50% in EtOAc) (0.550mL, 1.2eq), then add DIPEA(0.250mL, 2eq.).This limpid reaction mixture is stirred to 30min at-20 ℃.The progress of reaction is followed the tracks of by silica gel tlc analysis, is used in methylene dichloride 5% methyl alcohol as moving phase visual with UV, its be presented at and stir 30min at-30 ℃ after parent material exhaust.Reaction mixture is diluted with methylene dichloride, water (2x10mL) washing, organic layer is by dried over sodium sulfate and by concentrating to obtain crude compound (0.2g) under rotary evaporation (25 ℃, 20mm Hg).This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 2% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.01g productive rate (4.19%).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-((2-methylpyrimidine-5-yl) methyl) acrylamide: 1h NMR (400MHz, CDCl3) δ 9.02 (s, 1H), 8.65 (s, 2H), 8.52-8.59 (m, 3H), (7.15-7.17 d, J=10.8Hz, 1H), (6.02-6.04 d, J=10.4Hz, 1H), (4.69 s, 2H), 3.07 (s, 3H), 2.75 (s, 3H).C 20h 16f 6n 6the LCMS[M+H of O] +be 470.4; Be found to be 471.20 (at RT4.215min purity (91.16%)).
Example 19
Figure BDA0000484103910001681
(Z)-tertiary butyl 3-(3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acrylamido) methyl) piperidines-1-carboxylicesters (1) synthetic:
Figure BDA0000484103910001682
In a 50mL3 neck neck round-bottomed flask, add (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) and the tertiary butyl-3-(amino methyl) piperidines-1-carboxylicesters (0.134g) be dissolved in methylene dichloride (5.0mL) and add T3P(50%) (0.453g).Under nitrogen atmosphere, add DIPEA(0.147g).TLC by TCL analyzes (using 5% methyl alcohol: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.Reaction mixture is concentrated to provide a kind of white solid of 0.35g by rotary evaporation (40 ℃, 20mm Hg).Gained crude compound is used to silica gel 60/120 and methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode with methyl alcohol, since 2% to 4% methyl alcohol (in methylene dichloride), fraction collection).Compound starts wash-out with 3% methyl alcohol (in methylene dichloride).The part that comprises this kind of TLC profile is collected together to obtain compound (230mg), productive rate 80%.
(Z)-the tertiary butyl-3-((3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acrylamido) methyl) piperidines-1-carboxylicesters: 1h NMR (400MHz, DMSO) δ: 9.61 (s, 1H), 8.52-8.57 (q, 3H), 8.28 (s, 1H), 7.37-7.39 (d, J=10.4Hz, 1H), 5.95-5.97 (d, J=10.4Hz, 1H), 3.74-3.87 (br.s, 2H), 3.06 (s, 2H), 2.67-2.77 (m, 1H), 1.46 (brs, 2H), 1.31 (s, 9H).C 24h 27f 6n 5o 3lCMS[M+H] +be 547.49; Be found to be 548.6 (at RT3.51min purity (96.47%)).
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(piperidines-3-ylmethyl) acrylamide:
In a mono-neck round-bottomed flask of 25mL, by (Z)-tertiary butyl 3-((3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acrylamido) methyl) piperidines-1-carboxylicesters (1) (0.1g) is dissolved in methylene dichloride (5mL), and dropwise add be dissolved in the TFA(1.0mL in methylene dichloride).By silica gel tlc (using 10% methyl alcohol in methylene dichloride as moving phase) with the visual progress of following the trail of this reaction of UV.Reaction mixture is concentrated to provide 0.12g compound by rotary evaporation (40 ℃, 20mm Hg).The crude compound obtaining is carried out to purifying by ' SAEx ' column chromatography.Part is collected together to obtain compound (40mg), productive rate 49%.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(piperidines-3-ylmethyl) acrylamide 1h NMR (400MHz, DMSO) δ: 9.69 (s, 1H), (8.61 s, 2H), 7.94 (s, 1H), 7.13-7.16 (d, J=10.8Hz, 1H), 6.55 (s1H), 5.66-5.68 (d, J=10.8Hz, 1H), 3.23-3.37 (m, 2H), 2.98-3.10 (m, 2H), (2.58-2.65 t, 1H), 2.40-2.45 (t, 1H), 1.68-1.80 (m, 2H), 1.43-1.54 (m, 1H), 1.15-1.29 (m, 1H).C 19h 19f 6n 5the LCMS[M+H of O] +be 447.38; Be found to be 448.44 (at RT3.13min purity (99.12%)).
Example 20
Figure BDA0000484103910001701
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro pyrrolidin-1-yl) third-2-alkene-1-ketone synthetic: in a 100mL3 neck round-bottomed flask that disposes nitrogen entrance, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (4) (1g, 1.0eq.) pack in methylene dichloride (20mL, 20V).This reaction mixture is cooled to 0 ℃.In this reaction mixture, add HOBT(0.461g, 1.2eq.), EDC.HCl(0.819g, 1.5eq.), 3,3-difluoro pyrrolidine hydrochloride (0.490g, 1.2) and DIPEA(0.731mL, 1.5eq.).This limpid reaction mixture is stirred to 1.5h at 0 ℃.By TLC (use in methylene dichloride 5% methyl alcohol as moving phase) and by the visual progress of following the trail of this reaction of UV.By reaction mixture cancellation in water (50mL).Separate organic layer, and water layer is extracted with methylene dichloride (20 × 2).The organic layer of this merging is washed with salt brine solution, and use Na 2sO 4dry, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain the crude compound of 0.67g.This crude compound is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (25mL branch)) with MeOH.This compound starts wash-out from 0.9% to 1.0% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.115g productive rate (9.2%).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro pyrrolidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 9.25-9.30 (d, 1H), 8.59 (s, 2H), 7.94 (s, 1H), (7.17-7.28 m, J=10.8Hz, 1H), (5.82-5.91 m, J=10.8Hz, 1H), 3.78-4.00 (m, 4H), 2.41-2.54 (m, 2H); C 17h 12f 8n 4the LCMS[M+H of O] +be 440.29; Be found to be 441.39 (at RT2.982min purity (99.75%)).
Example 21
Figure BDA0000484103910001711
in
Synthesizing of mesosome-2
Figure BDA0000484103910001712
In a 250-mL3 neck round-bottomed flask disposing with the temperature meter base of nitrogen entrance and rubber septum adaptation, by DMF(40mL, 14.67eq.) be cooled to-10 ℃ and add POCl 3(10.58mL, 3.21eq.).This reaction mixture is stirred to 3h at 0 ℃.At 0 ℃, in this reaction mixture, add bromoacetic acid (5g, 1eq.).Gained reaction mixture is stirred to 6h at 85-90 ℃.After 6h has stirred, remove DMF by molecular distillation.Observe garnet resistates, resistates is cooled to room temperature, and add sodium tetrafluoroborate in this resistates, and observe heat release.Use ice bath that reactive material is cooling.Observe this solid residue (6.5g), by its filtration and be directly used in next step.
Synthesizing of intermediate-3
Figure BDA0000484103910001721
In a 100-mL3 neck round-bottomed flask disposing with the temperature meter base of water condenser, nitrogen entrance and rubber septum adaptation, by Wen Na meter Ding salt (vinamidium salt) (5.65g, 0.5eq.) and ethanamidine HCl(3g, 1eq) be dissolved in ethanol (30mL), and add sodium ethylate, the reaction mixture refluxed obtaining is stirred to 2-3h, the progress of reaction is followed the tracks of by silica gel tlc analysis, with 70% ethyl acetate-hexane, as moving phase, it is presented at parent material after 3h and exhausts.Under reduced pressure remove solvent, to provide thick material, be dissolved in the water, and by ethyl acetate, compound extracted.The organic layer of merging is dried with sodium sulfate, and under reduced pressure distills to obtain roughage.This roughage is stood to column purification, use silicon 60/120 as stationary phase and hexane: ethyl acetate is as moving phase.By this post filling hexane, and start wash-out in gradient mode with ethyl acetate, since 20% to 24% ethyl acetate (in hexane), fraction collection.Compound starts wash-out with 22% ethyl acetate (in hexane).The part that comprises this kind of TLC profile is collected together to obtain compound 700mg.
Synthesizing of intermediate-4
Figure BDA0000484103910001722
In a 50mL3 neck round-bottomed flask disposing with the temperature meter base of nitrogen entrance and rubber septum adaptation, at-30 ℃, to intermediate-3(1.0g, 1.0eq.) in add methyl-magnesium-bromide (2.47mL, 1.0eq.).By gained reaction mixture-30 ℃ of stirrings.The progress of reaction is followed the tracks of by silica gel tlc analysis, and with 70%EtOAc-hexane, as moving phase, it observes little parent material after being presented at 30min stirring, at 0 ℃ of temperature, reaction is stirred to 1h again.Reaction is carried out to cancellation with cold water, extract by ethyl acetate, be dried and under reduced pressure distill to obtain roughage with sodium sulfate.This roughage is stood to column purification, use silicon (60/120 order degree (mesh size)) as stationary phase and use ethyl acetate: hexane is as moving phase.In 25% ethyl acetate: hexane place required compound wash-out.The part that comprises this kind of TLC profile is collected together to obtain compound 1.5g, productive rate (82.41%); LCMS (%): residence time: 4.532min (84.82%) (M+H) +139.
Synthesizing of intermediate-5
Figure BDA0000484103910001731
In a 25mL3 neck round-bottomed flask disposing with the temperature meter base of nitrogen entrance and rubber septum adaptation,, by intermediate-4(0.25g, 1.0eq.) be dissolved in toluene (5mL).At 0 ℃ of temperature, in this reaction mixture, add diphenylphosphine acylazide compound (0.87mL, 2.4eq.) and DBU(0.65mL, 2.4eq.).Gained reaction mixture is stirred to 30min at 0 ℃, at room temperature stir 3-4h.The progress of reaction is followed the tracks of by silica gel tlc analysis, with 70%EtOAc-hexane as moving phase, its be presented at 4h after parent material exhaust.Reaction carried out in icy water to cancellation and extracted by ethyl acetate (50x3mL).The organic layer of merging is dried with sodium sulfate, and under reduced pressure concentrates to provide crude compound.Crude compound is stood to column chromatography, use ethyl acetate and hexane as moving phase.In 30% ethyl acetate (in hexane), compound is by wash-out.The part that comprises this kind of TLC profile is collected together to obtain compound 0.14g, productive rate (29.7%); LCMS (%): residence time: 2.454min (14.35%), (M+H) +164.
Synthesizing of intermediate-6
Figure BDA0000484103910001741
In a mono-neck round-bottomed flask of 25mL that is equipped with rubber septum, by intermediate-5(0140g), palladium carbon (0.07g) is suspended in methyl alcohol (2mL) and blasts wherein H 2.Gained reaction mixture is at room temperature stirred.The progress of reaction is followed the tracks of by silica gel tlc analysis, with 5% methyl alcohol-methylene dichloride and ammonia atmosphere as moving phase, its be presented at 15h afterwards parent material exhaust.To react by bed of diatomaceous earth (Celite Bed) and filter, filtrate is under reduced pressure concentrated to provide rough thing (0.19g).This roughage is stood to column purification, uses silicon as stationary phase and using MeOH: methylene dichloride together with 1%TEA as moving phase.At 2%MeOH: methylene dichloride together with 1%TEA as moving phase in required compound wash-out.The part that comprises this kind of TLC profile is collected together to obtain compound 0.09g, productive rate (76.9%). 1h NMR (400MHz, DMSO): δ=8.73 (s, 2H), 5.72 (broad peaks, 2HD2O is tradable), 4.187-4.23 (quartet, 2H), 2.6 (s, 3H), 1.38-1.4 (d, 3H); LCMS (%): LC-MS residence time: 5.457min (1.2%) (M+H) +138.
Figure BDA0000484103910001742
In a 250mL3 neck round-bottomed flask that disposes nitrogen entrance, pack intermediate 1(0.19g, 1.0eq. into) together with methylene dichloride (5mL, 10V).This reaction mixture is cooled to-20 ℃, and then add 1-(5-methylpyrimidine-2-yl) ethamine (0.09g, 1.2eq.), T3P(50% in EtOAc) (0.2mL, 1.2eq), then in this reaction mixture, add DIPEA(1.8mL, 2eq.).This limpid reaction mixture is stirred to 30min at-20 ℃.By silica gel tlc analysis (use 5% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of following the trail of this reaction of UV.Reaction mixture is concentrated to obtain crude compound by rotary evaporation (25 ℃, 20mm Hg).This crude reaction mixture is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and start wash-out in gradient mode (from fraction collection (500mL branch)) with MeOH.This compound starts wash-out from 5% methyl alcohol methylene dichloride.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.5gm productive rate (20%).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(1-(5-methylpyrimidine-2-yl) ethyl) acrylamide; 1h NMR (400MHz, DMSO) δ=9.48 (s, 1H), 9.01-8.99 (d, J=8Hz, 1H), 8.64 (s, 2H), 8.47 (s, 2H), 8.28 (s, 1H), 7.42-7.39 (d, J=10.4Hz, 1H), 6.01-5.99 (d, J=10.4Hz, 1H), 5.058 (m, 1H), 2.53 (s, 3H), 1.44-1.42 (d, J=7.2Hz, 3H) C 20h 16n 6f 6the LCMS[M+H of O] +be 470.35; Be found to be 471.49 (in RT2.775min purity 97.38%).
Example 22
(Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)-N-methyl-N-(oxazole-5-ylmethyl) acrylamide synthetic:
Figure BDA0000484103910001751
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-(oxazole-5-ylmethyl) acrylamide (0.15g, 0.34mmol) is dissolved in THF(30mL) in.This reaction mixture is cooled to 0 ℃; Add NaH(0.012g, 0.52mmol), and this reaction mixture is stirred to 0.5h.At the same temperature, dropwise add methyl-iodide (1.5mL).This limpid reaction mixture is further stirred at 0 ℃ to 1.5h.By reaction mixture segmentation in 20mL ice-water, and with DCM(3x50mL) extraction.The organic layer of these merging is washed and is used anhydrous Na with saturated brine 2sO 4dry, and under reduced pressure concentrate, to obtain the crude product of 0.180g, passed through column chromatography (0-2% methyl alcohol: DCM) and carried out purifying to provide (Z)-3-(3-(3 of 15mg, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-N-methyl-N-(oxazole-5-ylmethyl) acrylamide (productive rate: 9.6%). 1h NMR (400MHz, DMSO-d 6) δ=9.01 (s, 1H); 8.61 (s, 1H); 8.48 (s, 1H); 8.39 (s, 1H); 8.30 (s, 1H); 8.07 (s, 1H); (7.38-7.41 d, J=10Hz, 1H); 6.99 (s, 1H); (6.23-6.26 d, J=10Hz, 1H); 4.72 (s, 1H); 4.62 (s, 1H); (3.02 s, 3H) C 18h 14f 6n 5o 2lCMS[M+H] +be 446.32; Be found to be for 446.03 (residence times: 3.432min).
Example 23
Figure BDA0000484103910001761
In a 100mL3 neck round-bottomed flask that disposes nitrogen entrance, by intermediate-4(1g, 1.0eq.) be dissolved in methylene dichloride (20mL, 20V).This reaction mixture is cooled to 0 ℃.By HOBT(0.461g, 1.2eq.), EDC.HCl(0.819g, 1.5eq.), azetidine (0.195g, 1.2eq.) and DIPEA(0.731mL, 1.5eq.) be added in this reaction mixture, and this limpid reaction mixture is stirred to 1.5h at 0 ℃.By TLC (use 5% methyl alcohol as moving phase) in methylene dichloride and by the visual progress of monitoring reaction of UV.This reaction mixture is carried out in 50mL water to cancellation, separate dichloromethane layer, and methylene dichloride for water layer (20 × 2) is extracted.The organic layer of this merging is washed with salt brine solution, and use Na 2sO 4dry, and under reduced pressure concentrate by rotary evaporation (25 ℃, 20mmHg), to obtain the crude compound of 0.980g.This crude compound is used to 60/120 order silicon and using methyl alcohol: methylene dichloride carries out purifying as moving phase by column chromatography.By this post filling methylene dichloride, and carry out wash-out in gradient mode with MeOH.This compound starts wash-out from the 0.9%-1.0% methyl alcohol methylene dichloride.The part that comprises required TLC profile is collected together to obtain pure compound 0.225gm productive rate (20.25%).
(Z)-1-(azetidin-1-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ 9.87 (s, 1H), 8.62 (s; 2H), 7.93 (s, 1H); (7.18-7.20 d, J=10.8Hz, 1H); (5.65-5.68 d, J=10.8Hz, 1H); 4.26-4.30 (t, 2H), 4.16-4.20 (t; 2H), 2.34-2.42 (m, 2H); C 16h 12f 6n 4the LCMS[M+H of O] +be 390.28; Be found to be 391.39 (at RT2.935min purity (100%)).
Example 24
Figure BDA0000484103910001771
In a 50-mL3 neck round-bottomed flask that disposes nitrogen entrance and rubber septum, by intermediate-4(acid) be suspended in methylene dichloride (5mL).At-20 ℃, add intermediate-5a & DIPEA and T3P(50% in ethyl acetate), and this reaction mixture is stirred to 50-60min at the same temperature.Use 30% acetone-hexane to follow the trail of the progress of this reaction by TLC as moving phase.Then this reaction mixture is concentrated under 20mbar at 30 ℃ under vacuum, and by flash chromatography (using hexane & acetone as moving phase), gained crude compound is carried out to purifying.By this crude compound mixture with 15%-20% acetone-hexane wash-out out to obtain half pure compound, there is purity 55.91%(productive rate: 200mg); LCMS:m/z468.03 (M+1).Compound pure this half is further carried out to purifying to obtain 100mg by flash chromatography (using identical solvent ratio), it is further used to 30% acetone-hexane as moving phase by preparative TLC() carry out purifying, obtain 14mg product (productive rate 15%) 1h NMR (400MHz, DMSO-d 6, ppm) and δ=9.63 (s, 1H); 8.63-8.60 (t, 1H); 8.53 (s, 2H); 8.29 (s, 1H); (7.39-7.37 d, J=10.4Hz, 1H); (6.01-5.99 d, J=10.4Hz, 1H); (5.46-5.44 d, J=5.5Hz, 1H); 3.82-3.77 (m, 2H) 3.63-3.59 (m, 2H): C 21h 16f 6n 5the LCMS[M+H of O] +be calculated as 468.13; Be found to be for 468.3 (residence times: 3.719min).
Example 25
Figure BDA0000484103910001781
Under nitrogen atmosphere, in a 50-mL3 neck round-bottomed flask, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.529g, 0.91eq.) & 1-(azetidin-3-yl)-N, N-dimethyl methyl amine hydrochlorate (0.250g, 1.0eq) is dissolved in DMF(10mL, 15Vol) in.Then slowly add T3P(1.055g, 1.0eq.) be then DIPEA(0.748g, 3.5eq), and this reaction mixture is stirred to 30-45min at 0 ℃.Use 5% methyl alcohol in methylene dichloride with ammonia atmosphere as moving phase by TLC() confirm completing of this reaction.This reaction mixture is carried out in frozen water slurry to cancellation, extract by ethyl acetate, and wash this water layer by ethyl acetate (100mLX2).By the organic extract Na of these merging 2sO 4dry, filter and pass through rotary evaporation (40 ℃, 20mmHg) and concentrate, to obtain a kind of canescence semisolid (0.490g).Use 4% methyl alcohol and the methylene dichloride with ammonia atmosphere by preparative TLC() this product of purifying, to obtain 30mg compound (4.0%).
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino) methyl) azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz DMSO) δ 9.80-9.84 (d, J=17.6Hz, 1H); (8.62 s, 2H), 7.93 (s; 1H), 7.19-7.22 (d, J=10.4; 1H), 5.63-5.67 (d, J=10.8; 1H), 4.30-4.35 (t, 1H); (4.21-4.26 t, 1H), 3.89-3.93 (q; 1H), 3.76-3.80 (q, 1H); 2.84-2.87 (q; 1H), 2.50-2.61 (m, 2H); 2.24 (s, 6H); C 19h 19f 6n 5the LCMS[M+H of O] +be 447.38; Be found to be 448.05 (at RT3.77min purity (84.74%)).
Example 26
In a 50mL3 neck neck round-bottomed flask, under nitrogen atmosphere, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (intermediate-4) (0.200g, 1.0eq.) and (1-methyl piperidine-4-yl) methylamine (0.073g, 1eq.) be suspended in methylene dichloride (10.0mL), and add T3P(50%) (0.432g, 1.2eq.), keep-40 ℃, then add DIPEA(0.147g, 2.0eq.).TLC by TCL analyzes (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.This reaction mixture is concentrated to provide the one oil of 0.250g by rotary evaporation (35 ℃, 20mmHg).Use and there is the methyl alcohol of ammonia atmosphere by preparative TLC(: methylene dichloride (5:5) is as moving phase) gained crude compound is carried out to purifying, obtain 40mg(productive rate-15%) pure compound; (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-((1-methyl piperidine-4-yl) methyl) acrylamide: 1h NMR (400MHz, DMSO) δ, 9.59 (s; 1H), 8.52 (s, 2H); (8.46-8.49 t, 1H), 8.29 (s; 1H), 7.35-7.37 (d, J=10.4Hz; 1H), 5.95-5.98 (d, J=10.4Hz; 1H), 3.03-3.06 (m, 2H); (2.67-2.70 m, 2H), 2.09 (s; 3H), 1.69-1.74 (m, 2H); 1.56-1.59 (m; 2H), 1.07-1.17 (m, 2H); C 20h 21f 6n 5the LCMS[M+H of O] +be 461.4; Be found to be 462.5 (at RT3.69min purity (94.31%)).
Example 27
Figure BDA0000484103910001801
In a 50mL3 neck round-bottomed flask, under nitrogen atmosphere, by intermediate-4(acid) (0.100g, 1.0eq.) and (1-methyl piperidine-3-yl) methylamine (0.036g, 1.0eq.) be suspended in methylene dichloride (10.0mL), then at-40 ℃, add T3P(50%) (0.216g, 1.2eq.) and DIPEA(0.073g, 2.0eq.).TLC by TCL analyzes (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.This reaction mixture is concentrated to provide the one oil of 0.120g by rotary evaporation (35 ℃, 20mmHg).Use and there is the methyl alcohol of ammonia atmosphere by preparative TLC(: methylene dichloride (5:5) is as moving phase) gained crude compound is carried out to purifying, obtain 11mg(productive rate-15%) pure compound; (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-((1-methyl piperidine-3-yl) methyl) acrylamide: 1h NMR (400MHz, DMSO) δ, 9.72 (s, 1H), 8.61 (s, 2H), (7.94 s, 1H), 7.14-7.16 (d, J=10.8Hz, 1H), 5.66-5.68 (d, J=10.8Hz, 1H), 3.71-3.76 (m, 2H), 3.31 (m, 2H), (2.73-2.79 m, 2H), 2.26 (s, 3H) 2.02 (m, 1H), 1.87 (m, 2H), (1.73 m, 2H) C 20h 21f 6n 5the LCMS[M+H of O] +be 461.4; Be found to be 462.5 (at RT3.81min purity (88.64%)).
Example 28
(Z)-6,7-dihydro-5H-cyclopenta [b] pyridine-5-ketoxime synthetic
Figure BDA0000484103910001802
In a 100-mL3 neck round-bottomed flask, at room temperature, 6,7-dihydro-5H-cyclopenta [b] pyridine-5-ketone (2.0g, 1.0eq.) is dissolved in to EtOH(24.0mL) and H2O(6.0mL) in.Then at the same temperature, add sodium acetate trihydrate (8.175g, 4.0eq.) and hydroxy amine hydrochloric acid salt (4.174g, 4.0eq.).TLC by TCL analyzes (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.By the cancellation extracting by methylene dichloride in 50mL water of this reaction mixture.Organic layer is concentrated to provide 2.10g crude compound by rotary evaporation (35 ℃, 20mm Hg), it is not carried out to purifying and is used in next step.
Synthesizing of 6,7-dihydro-5H-cyclopenta [b] pyridin-5-amine
Figure BDA0000484103910001811
In a 50mL3 neck round-bottomed flask, intermediate steps (1) (1.0g, 1.0eq.) is dissolved in to MeOH(15.0mL, 15V) in.In this reaction mixture, add at the same temperature six water nickelous chlorides (0.010g).By this reaction mixture be cooled to-40 ℃ and at the same temperature through 30min branch add NaBH4(2.5g, 10.0eq.).TLC by TCL analyzes (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.By the cancellation extracting by ethyl acetate in 50mL water of this reaction mixture.This organic phase is concentrated to provide 0.64g crude compound by rotary evaporation (35 ℃, 20mm Hg), it is not carried out to purifying and be used in next step.
Figure BDA0000484103910001812
In a 100mL3 neck round-bottomed flask that disposes nitrogen entrance, this acid (0.327g, 1.0eq.) is dissolved in methylene dichloride (20mL).In this reaction mixture, add (1a) (0.150g, 1.2eq.), and this reaction mixture is cooled to-70 ℃.Dropwise add T3P(propyl phosphonous acid acid anhydride) (0.665mL, 1.2eq.), then add DIPEA(0.318mL, 2.0).By silica gel tlc analysis (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.By the cancellation extracting by methylene dichloride in 50mL water of this reaction mixture.This organic layer is concentrated to provide 0.369g crude compound by rotary evaporation (35 ℃, 20mmHg), it is carried out to purifying by column chromatography.Locate this product wash-out to provide 0.017g pure products at 0.6% methyl alcohol (in methylene dichloride).(productive rate 3.90%); (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-(6,7-dihydro-5H-cyclopenta [b] pyridine-5-yl) acrylamide: 1h NMR (400MHz, DMSO) δ 9.61 (s, 1H), (9.03-9.01 d, 1H), 8.54 (s, 2H), 8.49-8.47 (d, 1H), (8.307 s, 1H), 8.02-8.00 (d, 1H), 8.19-8.18 (m, 1H), (7.45-7.42 d, J=10.4Hz, 1H), (5.97-5.45 d, J=10.4Hz, 1H), (5.53-5.47 m, 1H), 3.12-3.03 (m, 1H), 2.50-2.28 (m, 2H), 2.03-2.02 (m, 1H).C 21h 15f 6n 5the LCMS[M+H of O] +be found to be 480.44 (at RT3.21min purity (95.48%)).
Example 29
Synthesizing of 1-(pyrazine-2-yl) ethamine
Figure BDA0000484103910001821
At room temperature, be equipped with magnetic agitation and a kind of immerseable thermometer to one, in 1-(pyrazine-2-yl) ethyl ketone (1.0g, 1.0eq.) and 3 neck 100mL round-bottomed flasks MeOH(30mL), add ammonium acetate (6.31g, 10eq.).In this reaction mixture, add sodium cyanoborohydride (0.360g, 0.7eq.) and reactive material is at room temperature stirred and spent the night.The progress of reaction is monitored by silica gel tlc analysis, uses MeOH: methylene dichloride (2.5%) is as moving phase visual with UV, SM Rf=0.70 and product Rf=0.20.This reaction mixture is concentrated and be poured in water (100mL) and use NaOH aqueous solution alkalization (PH=13).By gained for mixture methylene dichloride (2x100mL) extract, and by salt brine solution for organic layer (2x50mL) washing of these merging, use MgSO 4dry, filter, and concentrate by rotary evaporation, to obtain the amine productive rate 30% of wanting of 0.3g.
In one is disposed in the 3 neck round-bottomed flasks of the 100mL of, nitrogen bubble device and thermometer pocket, by intermediate-1A(0.300g, 1.0eq.) be dissolved in methylene dichloride (20mL).Add a second section (0.126g, 1.2eq.) of intermediate-1A, and this reaction mixture is cooled to-60 ℃.At the same temperature, in this reaction mixture, add T 3p(propyl phosphonous acid acid anhydride) (0.60mL, 1.2eq.) and DIPEA(0.29mL, 2.0eq.), and this mixture is stirred to 30min.The progress of reaction is followed the tracks of by silica gel tlc analysis, uses 5%MeOH: methylene dichloride is as moving phase visual with UV, SM Rf=0.20 and product Rf=0.50.Then this reaction mixture is poured in water (100mL) and extracts with methylene dichloride (2x100mL).By salt brine solution for organic layer (2X50mL) washing of these merging, use anhydrous MgSO 4dry, filter, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain crude compound, passed through column chromatography (diameter: 2.5cm) and used silicon 60/120 and MeOH: methylene dichloride is carried out purifying as moving phase.Column purification starts from 0.5%MeOH methylene dichloride, up to 2.0%MeOH in methylene dichloride.The product of wanting starts wash-out with 1.5%MeOH.Under 40 ℃/250mm Hg, utilize rotary evaporation the part that contains this compound to be distilled to obtain 0.2g pure compound, productive rate: 51.4%; (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-) 1H-1,2,4-triazol-1-yl)-N-(1-(pyrazine-2-yl) ethyl) acrylamide: 1h NMR (400MHz, DMSO) δ, 9.52 (s; 1H), 8.28-9.13 (m, 6H); (7.40-7.42 d, J=10.4Hz, 1H); (6.04-6.07 d, J=10.4Hz, 1H); 5.12-5.19 (m; 1H), 1.46-1.47 (d, 3H); C 19h 14f 6n 6the LCMS[M+H of O] +be 456.3; Be found to be 457.44 (at RT2.894min purity (99.91%)).
Example 30
Figure BDA0000484103910001841
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-((1-methylpyrrolidin-3-yl) methyl) acrylamide:
In a 50mL3 neck round-bottomed flask, by (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) and (1-methylpyrrolidin-3-yl) methylamine (0.035g, 1.1eq) be dissolved in DMF(10mL) in and under nitrogen atmosphere, add PYBROP(0.140g, 1.1eq.) and DIPEA(0.073mg, 2.0eq.).By silica gel tlc analysis (use has 0.5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of following the trail of this reaction of UV light.By the cancellation in frozen water of this reaction mixture, compound is extracted by ethyl acetate (25x3mL), use anhydrous Na 2sO 4dry, filter, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain the rough thing of solid of 0.232g.Reach purifying via column chromatography with methylene dichloride and methyl alcohol.Locate compound at 10% methyl alcohol (in methylene dichloride) with ammonia and start wash-out.At 25 ℃, under 20mm Hg, utilize rotary evaporation that the cut that contains compound is distilled to obtain 98.0mg pure compound.Productive rate 77%; (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-((1-methylpyrrolidin-3-yl) methyl) acrylamide: 1h NMR (400MHz, DMSO) δ 9.83 (s, 1H), (8.61-8.65 d, J=12.4Hz, 2H), 7.93 (s, 1H), 7.31-7.15 (d, J=10.8Hz, 1H), 5.69-5.71 (d, J=10.8Hz, 1H), 3.34-3.43 (m, 2H), 2.87-2.91 (m, 1H), (2.63-2.65 d, J=9.2Hz, 1H), 2.41-2.54 (m, 2H), 2.73 (s, 3H), 2.05-2.11 (m, 2H), (1.71 s, 1H), C 19h 19f 6n 5the LCMS[M+H of O] +be 447.24; Be found to be 448.26 (at RT6.50min purity (89.08%)).
Example 31
Figure BDA0000484103910001851
In a 50mL3 neck round-bottomed flask, by intermediate 4(0.2g, 1.0eq.) add methylene dichloride to: in ethyl acetate (25.0mL, 1:1).Then at-40 ℃, add (2-methylpyrimidine-5-yl) methylamine (0.078g, 1eq.).Then add at the same temperature T3P(50% ethyl acetate (0.432g, 1.2eq.) and DIPEA(0.147g, 2.0eq. simultaneously) and this reaction mixture is stirred to 30min at-40 ℃.By TLC (use has 5% methyl alcohol of ammonia atmosphere: methylene dichloride is as moving phase) and by the visual progress of monitoring this reaction of UV light.This reaction mixture is concentrated to provide the one oil of 0.270g by rotary evaporation (35 ℃, 20mmHg).By column chromatography (using methylene dichloride: methyl alcohol is as moving phase) purifying gained crude mixture, locate this compound wash-out at 4% methyl alcohol (in methylene dichloride).The compound that comprises each several part is under reduced pressure concentrated, to obtain 80mg(productive rate-29.85%) pure compound.
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-N-((2,4-dimethyl pyrimidine-5-yl) methyl) acrylamide: 1h NMR (400MHz, DMSO) δ, 9.57 (s, 1H), 8.91-8.94 (t; 1H), 8.51 (s, 2H), 8.43 (s; 1H), 8.29 (s, 1H), 7.40-7.42 (d; J=10.4Hz, 1H), 5.98-6.01 (d, J=10.4; 1H), 4.37-4.38 (d, J=5.6Hz, 2H); (3.35 s, 3H), 2.50 (s, 3H); C 20h 16f 6n 6the LCMS[M+H of O] +be 470.37; Be found to be 471.25 (at RT2.69min purity (99.89%)).
Example 32
(Z)-3-(3-(4-is chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone synthetic
Figure BDA0000484103910001861
In a 50mL3 neck round-bottomed flask that disposes nitrogen entrance, by intermediate-3(0.1g, 1.0eq.) be dissolved in DMF(5mL) in.In this reaction mixture, add DABCO(0.071g, 2eq.), and stir 30min.Then add (Z)-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (0.095g, 1.1eq.), and by this reaction mixture at stirring at room temperature 5h.By TLC (use methylene dichloride: methyl alcohol (9.5:0.5) moving phase) and by the visual progress of following the trail of this reaction of UV.This reaction mixture is poured in frozen water (50mL), then uses EtOAc(3X15mL) extract.By salt brine solution for organic layer (20mL) washing of these merging, use Na 2sO 4dry, filter, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain the crude compound of 0.150g, it is carried out to purifying by preparative TLC and obtain pure compound 0.004g, productive rate (3%).
(Z)-3-(3-(4-is chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, DMSO) δ=9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J=10.4Hz, 1H), 6.00-5.04 (d, J=10.4Hz, 1H), 4.55-4.58 (m, 2H), (4.33-4.36 m, 2H) C 16h 9clF 8n 4the LCMS[M+H of O] +be 460.7; Be found to be for 461.14 (purity 98.77% is in the 2.99min residence times)
Example 35
Figure BDA0000484103910001862
In a 25ml sealed tube, by NaH(0.064g, 1.5eq.) be suspended in THF(10mL) in, and be then cooled to 0 ℃.To in this mixture at 0 ℃ of intermediate 3(0.3g, 1.0eq. being dropwise added in THF) solution, and then by this mixture reflux 2h at 80 ℃.Analyze (use 10% ethyl acetate as moving phase) in hexane and follow the trail of the progress of this reaction by TLC.Then this reaction mixture is concentrated and is used ethyl acetate (2X150mL) extraction gained material.By salt brine solution for organic layer (2X100mL) washing of these merging, use anhydrous Na 2sO 4dry, filter, and concentrate by rotary evaporation (40 ℃, 20mmHg), to obtain a kind of crude mixture of 0.43g.By column chromatography (using the ethyl acetate in hexane), this mixture is carried out to purifying.This compound wash-out in 25% ethyl acetate isohexane, uses this cis-product to be separated by the moving phase that in hexane, 10% acetone forms via preparative TLC.The pure products obtaining is 0.016g; (Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ, 8.78-8.79 (d, J=2.4; 1H), 8.28 (s, 2H); (7.19-7.22 d, J=10.8Hz, 1H); (6.81-6.82 d, J=2.4,1H); (5.44-5.47 d, J=10.8Hz, 1H); 4.44-4.51 (m, 4H); C 17h 11f 8n 3the LCMS[M+1 of O] +be 425.28; Be found to be 426.09 (at RT3.202min purity (22.42%)).
Example 40
Figure BDA0000484103910001871
In a 25mL3 neck round-bottomed flask that disposes partition, nitrogen bubble device and temperature meter base, add intermediate 1(acid) (0.080g, 1.0eq.) and methylene dichloride (6.0mL).Then add 3,3-difluoro azetidine .HCl(0.0.035g, 1.2eq.), and this reaction mixture is cooled to-60 ℃.At the same temperature, in this mixture, add T 3p(propyl phosphonous acid acid anhydride) (0.161ml, 1.2eq.) and DIPEA(0.077mL, 2.0eq.), and gained mixture is stirred to 1h.The progress of reaction is analyzed to follow the tracks of by TLC, uses 5%MeOH: methylene dichloride is as moving phase visual with UV, SM Rf=0.20 and product Rf=0.70.Then this reaction mixture is poured over to D 2o(10mL) in and with methylene dichloride (2X20ml), extract.By the anhydrous MgSO of the organic layer of these merging 4dry, filter, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain a kind of crude compound, it is used to silicon 60/120 and MeOH by column chromatography: methylene dichloride carries out purifying as moving phase.Column purification starts from 1.5%MeOH methylene dichloride, up to 2.0%MeOH in methylene dichloride.Start wash-out and utilize rotary evaporation the part that contains compound to be distilled to obtain 0.020g pure compound, productive rate under 40 ℃/250mm Hg at wanted product at 1.5% methyl alcohol: 20%. 1h NMR (400MHz, CDCl 3) δ 9.63-9.66 (d, J=10.8Hz, 1H), 8.61 (s, 2H); 7.95 (s, 1H), 7.24-7.27 (t, J=4.4Hz, 1H); 5.67-5.69 (d, J=10.8Hz, 1H), 4.46-4.60 (m, 4H); Chemical formula: C 16h 8d 2f 8n 4the LCMS[M+H of O] +be 428.28; Be found to be 429.14 (RT2.992min, purity (98.62%)).
Example 43
Figure BDA0000484103910001881
Synthesizing of intermediate (1)
Figure BDA0000484103910001891
In a 100-mL3 neck RBF who disposes nitrogen entrance, temperature meter base and stopper, two 3,5-(trifluoromethyl)-benzyl cyanides (1.4mL, 1.0eq.) are dissolved in to THF(20mL, 10V) in.This reaction mixture is cooled to-78 ℃.In this reaction mixture, dropwise add NaHMDS(35% in THF) (4.34mL, 1.05eq.).After completing interpolation, make reaction mixture to 10 ℃ and stir 15min.Again this reaction mixture is cooled to-78 ℃ and add ethyl bromoacetate (0.87mL, 1.0eq.).Make reaction mixture to room temperature.This reaction mixture is at room temperature stirred to 16hr.Analyze (use 20% ethyl acetate-hexane as moving phase) and follow the trail of the progress of this reaction by TLC.Reaction mixture is poured in water (50mL) and with EtOAc(3x20mL) extract.By salt brine solution for organic layer (50mL) washing of this merging, use anhydrous Na 2sO 4dry, filter, and concentrate by rotary evaporation, to obtain the crude compound of 3.5g.This crude compound is used to 60/120 order silicon and using ethyl acetate: hexane carries out purifying as moving phase by column chromatography.By this post filling hexane, and start wash-out in gradient mode (from fraction collection (25-mL part)) with ethyl acetate.By this compound since 4% to 6% ethyl acetate (in hexane) wash-out.The part that comprises this kind of TLC profile is collected together to obtain pure compound 1.2gm productive rate (44.94%).
Synthesizing of intermediate (2)
In a 100-mL3 neck RBF who disposes nitrogen entrance, temperature meter base and stopper, intermediate-1 (1.2g, 1.0eq.) is dissolved in to MeOH(48mL, 40V) in.Portion-wise addition dichloro cobalt hexahydrate (1.68g, 2.0eq.).This reaction mixture is cooled to 20 ℃.Maintain the temperature at below 25 ℃, by NaBH 4(1.98g, 15eq.) lentamente portion-wise addition in this reaction mixture.Then this reaction mixture is stirred to 18hr at 25 ℃.Analyze (use 50% ethyl acetate-hexane as moving phase) and follow the trail of the progress of this reaction by TLC.Under reduced pressure concentrated this reaction mixture, and resistates segmentation between ethyl acetate (25mL) and water (25mL).Reaction mixture by diatomite filtration and separate organic layer, is used to anhydrous Na 2sO 4dry, filter, and concentrate by rotary evaporation.This crude compound is ground to provide 0.5g pure compound with pet ether.(productive rate 47.61%).
Synthesizing of intermediate (3)
Figure BDA0000484103910001901
In a 100-mL3 neck RBF who disposes nitrogen entrance, temperature meter base and stopper, by intermediate-2(1.0g, 1.0eq.) be dissolved in THF(20mL, 20V) in.This reaction mixture is cooled to 0 ℃.0 ℃ of holding temperature is dropwise added LAH(6.7mL, 2eq. in this reaction mixture).Complete after interpolation, by the temperature of reaction mixture to room temperature and be then back to 70 ℃ of 1h.Analyze (use 5%MeOH:DCM as moving phase) and follow the trail of the progress of this reaction by TLC.This reaction mixture is cooled to 0 ℃.Reaction mixture is carried out to cancellation by adding 1.5mL5%KOH solution.Then mixed reaction material filtered by diatomite and use EtOAc(20mL) wash.Filtrate is concentrated to obtain 1.0g crude compound by rotary evaporation.This crude compound is used to 60/120 order silicon and carries out purifying using MeOH:DCM as moving phase by column chromatography.By this post filling DCM, and start wash-out in gradient mode (from fraction collection (25-mL branch)) with MeOH.This compound since 4% to 6%MeOH(in DCM) wash-out.The part that comprises this kind of TLC profile is collected together to obtain pure compound 0.18gm productive rate (19%).
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-) pyrrolidin-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910001911
In the 3 neck round-bottomed flasks of a 50mL who disposes partition, nitrogen bubble device and temperature meter base, be added on DMF(2mL) in intermediate-3(0.050g, 1.0 equivalents).Then at room temperature, add DABCO(0.039g, 2.0eq.).Reaction mixture is at room temperature stirred to 30min.At room temperature, dropwise add intermediate-1A(0.053g, 1.1eq.).Reaction mixture is stirred to 30min.The progress of reaction is analyzed to follow the tracks of by TLC, uses 5%MeOH:DCM as moving phase visual with UV, SM Rf=0.20 and product Rf=0.70.This reaction mixture is poured in water (50mL) and with EtOAc(2X50mL) extract.By salt brine solution for organic layer (50mL) washing of this merging, use anhydrous Na 2sO 4dry, filter, and concentrate by rotary evaporation (25 ℃, 20mm Hg), to obtain crude compound 50mg.Use 2%MeOH:DCM as moving phase by preparative TLC() this roughage is carried out to purifying.By preparative TLC(use 50%EtOAc: hexane is as moving phase) by its again purifying with obtain 0.018g pure compound (productive rate-24%).
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-) pyrrolidin-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone: 1h NMR (400MHz, CDCl 3) δ, 7.82 (s, 1H), 7.73 (s; 1H), 7.69 (s, 2H), 4.43-4.46 (d; J=12.4Hz, 1H), 4.32-4.38 (t, J=12Hz; 4H), 3.61 (s, 2H), 2.47 (s; 1H), 2.18 (s, 1H), 2.16 (s; 1H), 1.27 (s, 1H); C 18h 16f 8n 2the LCMS[M+1 of O] +be 428.3; Be found to be 429.09 (at RT3.047min purity (95.45%)).
Example 44
Figure BDA0000484103910001921
Synthesizing of ethyl 3-(two (trifluoromethyl) phenyl of 3,5-)-3-cyanopropionic acid ester (1):
Two 3,5-(trifluoromethyl)-benzyl cyanides (1.4mL, 1.0eq.) are dissolved in to THF(20mL) in.This reaction mixture is cooled to-78 ℃, dropwise adds wherein NaHMDS(35% in THF) a kind of solution of (4.34mL, 1.05eq.).Allow this reaction mixture heat to 10 ℃ and stir 15min.Then be cooled to-78 ℃, added wherein ethyl bromoacetate (0.87mL, 1.0eq.).Then allow this reaction mixture to heat to room temperature, stirred 16h herein.Reaction mixture is poured in water (50mL) and with EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use anhydrous Na 2sO 4dry, filter and under reduced pressure concentrate, to obtain the crude product of 3.5g, passed through chromatography (4% ethyl acetate in hexane) and carried out purifying to provide ethyl 3-(two (trifluoromethyl) phenyl of 3, the 5-)-3-cyanopropionic acid ester (productive rate 44.94%) of 1.2g.
Synthesizing of 4-(two (trifluoromethyl) phenyl of 3,5-) pyrrolidin-2-one (2):
Figure BDA0000484103910001931
Ethyl 3-(two (trifluoromethyl) phenyl of 3,5-)-3-cyanopropionic acid ester (1.2g, 1.0eq.) is dissolved in to MeOH(48mL) in.Add dichloro cobalt hexahydrate (1.68g, 2.0eq.) and this reaction mixture is cooled to 20 ℃.Maintain the temperature at below 30 ℃ portion-wise addition NaBH 4(1.98g, 15eq.).After completing interpolation, this reaction mixture is stirred to 18h at 25 ℃.Under reduced pressure concentrated this reaction mixture, and this resistates segmentation between ethyl acetate (25mL) and water (25mL).This reaction mixture is passed through to Celite tMfilter, and separate this organic layer, use anhydrous Na 2sO 4dry, filter and under reduced pressure concentrate, to obtain the crude product of 0.65g, after being ground with sherwood oil, it provides 4-(two (trifluoromethyl) phenyl of 3, the 5-) pyrrolidin-2-one (productive rate 47.61%) of 0.5g.
(E) synthesizing of-4-(two (trifluoromethyl) phenyl of 3,5-)-1-(3-(3,3-difluoro azetidin-1-yl)-3-oxygen third-1-thiazolinyl) pyrrolidin-2-one
Figure BDA0000484103910001932
4-(3,5-two (trifluoromethyl) phenyl) pyrrolidin-2-one (0.5g, 1.0eq.) is dissolved in to DMF(5mL) in and be cooled to 0 ℃.At 0 ℃, be added on DMF(0.133g, 2.0eq.) in NaH.Then introduce (Z)-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (0.689g, 1.5eq.) at this reaction mixture of stirring at room temperature 30min.This reaction mixture is poured in water (50mL) and with EtOAc(3x20mL) extract.By salt solution for organic layer (3x50mL) washing of these merging, use anhydrous Na 2sO 4dry, filter and under reduced pressure concentrate, to obtain the crude product of 0.502g, passed through chromatography (1% methyl alcohol in DCM) and carried out purifying to provide (E)-4-(3 of 0.030g, two (trifluoromethyl) phenyl of 5-)-1-(3-(3,3-difluoro azetidin-1-yl)-3-oxygen third-1-thiazolinyl) pyrrolidin-2-one (productive rate 4.03%). 1h NMR (400MHz, CDCl 3) δ 8.15-8.19 (d, J=14Hz, 1H), 7.69-7.87 (m; 3H), 5.27-5.31 (d, J=14Hz, 1H); 4.05-4.47 (m, 4H), 3.89-3.93 (s; 1H), 3.73-3.77 (s, 1H); 3.60-3.62 (s, 1H), 3.08-3.13 (s; 1H), 2.78-2.90 (s, 1H); C 18h 14f 8n 2o 2lCMS[M+H] +be calculated as 443.44, residence time 2.97min.
Example 51
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxyl-3-(trifluoromethyl) azetidin-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910001941
By (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.10g, 1.0eq.) and 3-(trifluoromethyl) aza-cyclobutane-3-alcohol hydrochloride (0.055g, 1.1eq.) be dissolved in DCM(3.0mL) in.This reaction mixture is cooled to-30 ℃, now adds T 3p(0.3mL, 1.5eq) and DIPEA(0.12mL, 2eq.).This reaction mixture is stirred to 30min at-30 ℃, and dilute by DCM, wash with water.The organic layer of these merging is dried with sodium sulfate, and distills to obtain crude product under decompression (250 ℃, 20mm Hg).By this crude product by preparative TLC(70% ethyl acetate-hexane) carry out purifying, provide (Z)-3-(3-(3 of 0.020g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxyl-3-(trifluoromethyl) azetidine-1-yl) third-2-alkene-1-ketone.(productive rate: 14.8%). 1h NMR (400MHz, MeOD) δ 9.20 (s, 1H); 8.65 (s, 2H), 8.09 (s; 1H), 7.40-7.43 (d, J=10Hz; 1H), 5.95-5.93 (d, J=10.6Hz; 1H), 4.42-4.43 (m, 2H); 4.33-4.05 (m, 2H); C 17h 11f 9n 4o 2lCMS[M+H] +be calculated as 474.3; Be found to be for 475.14 (residence times: 2.872min),
Synthesizing of 1-diphenyl-methyl-3-(trifluoromethyl) aza-cyclobutane-3-alcohol (1A)
Figure BDA0000484103910001951
1-dibenzo-p-methyl-aza-cyclobutane-3-ketone (5.0g, 1.0eq.) is dissolved in to THF(50mL) in.Add trifluoromethyl trimethyl silane at 5 ℃-10 ℃.This reaction mixture is stirred to 10min at 10 ℃.Then add tetrabutyl ammonium fluoride.Allow this reaction mixture to be heated to room temperature and stir 1h.This reaction mixture is diluted by ethyl acetate and water and salt solution wash.By this organic layer dried over sodium sulfate, and under reduced pressure concentrate, to provide crude product, passed through chromatography (6% ethyl acetate-hexane) and carried out purifying to provide 1-diphenyl-methyl-3-(trifluoromethyl) aza-cyclobutane-3-alcohol (productive rate: 46.32%) of 3g.
Synthesizing of 3-(trifluoromethyl) aza-cyclobutane-3-alcohol hydrochloride (2a)
Figure BDA0000484103910001952
1-diphenyl-methyl-3-(trifluoromethyl) aza-cyclobutane-3-alcohol (0.25g) is dissolved in ethanol (3mL).Add the palladium hydroxide (0.25g) on charcoal, and blast hydrogen in this reaction mixture.This reaction mixture is maintained to 25-30 ℃ of 2h.Remove the solid forming by filtration, and in this filtrate, add ethanol HCl and further stir 30min at 0 ℃.This reaction mixture is under reduced pressure concentrated to provide a kind of oily resistates, it is ground to provide 3-(trifluoromethyl) aza-cyclobutane-3-alcohol hydrochloride with ether, for solid product, it is not further purified and for next step. 1H-NMR(400MHz,MeOD)δ=4.39-4.43(d,2H),4.13-4.16(d,2H)。
Example 52
(Z)-tertiary butyl 6-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiroheptane-2-carboxylicesters (3.3) synthetic
Figure BDA0000484103910001961
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.50g, 1.0eq.) is dissolved in to DCM(5mL) in.Add tert-butyl 2,6-diaza spiroheptane-2-carboxylate hydrochloride (0.40g, 1.2eq.) is also cooled to-70 ℃ by this reaction mixture.Dropwise add T3P(1.02mL, 1.2eq.), then add DIPEA(0.73mL, 3.0eq.).This reaction mixture is gone out and extracted by DCM with 50mL shrend.This organic layer is being reduced pressure (35 ℃, 20mm Hg) under concentrate, to obtain the crude product of 0.603g, passed through chromatography (1% methyl alcohol in DCM) and carried out purifying to provide (Z)-tertiary butyl 6-(3-(3-(3 of 0.350g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiroheptane-2-carboxylicesters.(productive rate 46.29%).
(Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diaza spiro [3.3] heptan-2-yl) third-2-alkene-1- ketone 2,2,2-trifluoro-acetate synthetic:
By (Z)-tertiary butyl 6-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiroheptane-2-carboxylicesters (0.13g) is dissolved in DCM(1.5mL) in.This reaction mixture is cooled to 0 ℃ and interpolation CF 3cOOH(1.5mL).Allow this reaction mixture to heat to room temperature, now stirred 4h.This reaction mixture is being reduced pressure (35 ℃, 20mm Hg) under concentrate to obtain (Z)-3-(3-(3 of 0.100g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(2,6-diaza spiro [3.3] heptan-2-yl) third-2-alkene-1- ketone 2,2,2-trifluoro-acetate (productive rate 95.23%). 1h NMR (400MHz, DMSO) δ 9.49 (s, 1H); 8.52-8.5 (m, 3H), 8.32 (s; 1H), 7.44-7.42 (d, 1H; J=10.4Hz), 5.97-5.94 (d, J=10.4Hz; 1H;), 4.37-3.93 (m, 8H); C 18h 16f 6n 5the LCMS[M+H of O] +be calculated as 432.34; Be found to be for 432.29 (residence times: 2.256min).
Example 53
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy azetidine-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910001971
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) is dissolved in to DCM(20mL) in.This reaction mixture is cooled to-60 ℃, now dropwise adds aza-cyclobutane-3-alcohol hydrochloride (0.075g, 1.2eq), T3P(50% in EtOAc) (0.4mL, 1.2eq), be then DIPEA(0.2mL, 2eq.).This limpid reaction mixture is stirred to 45min at-60 ℃.This reaction mixture is being reduced pressure (25 ℃, 20mm Hg) under concentrate, to obtain crude product, passed through chromatography (thering is 5% methyl alcohol in DCM of ammonia) and carried out purifying to obtain (Z)-3-(3-(3 of 30mg, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy azetidine-1-yl) third-2-alkene-1-ketone, productive rate (13%). 1h NMR (400MHz, DMSO) δ=9.4 (s, 1H), 8.56 (s, 2H), 8.29 (s, 1H), 7.48-7.40 (d, J=10.4Hz, 1H), 5.95-5.97 (d, J=10Hz, 1H), 5.77-5.79 (d, J=5.6,1H, D 2o is tradable), 4.47-4.48 (d, J=5.6,1H), 4.25-4.29 (t, 1H), 4.15-4.19 (m, 1H), 3.8-3.84 (m, 1H), 3.70-3.73 (m, 1H); C 16h 13f 6n4O 2lCMS[M+H] +be calculated as 407.28; Be found to be for 407.14 (residence times: 2.462min).
Example 54
(Z) synthesizing of-1-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-nitrile
Figure BDA0000484103910001981
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.2g, 1.0eq.) is dissolved in to DCM(20mL) in.This reaction mixture is cooled to-60 ℃, now dropwise adds azetidine-3-nitrile hydrochloride (0.08g, 1.2eq), T3P(50% in EtOAc) (0.4mL, 1.2eq), be then DIPEA(0.2mL, 2eq.).This limpid reaction mixture is stirred to 45min at-60 ℃.This reaction mixture is being reduced pressure (25 ℃, 20mm Hg) under concentrate, to obtain crude product, passed through chromatography (the 3%-5% methyl alcohol in DCM) and carried out purifying to obtain (Z)-1-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-nitrile, (0.14g, 60% productive rate). 1h NMR (400MHz, DMSO) δ=9.36 (s, 1H), 8.54 (s; 2H), 8.30 (s, 1H); (7.45-7.43 d, J=10Hz, 1H); (5.95-5.92 d, J=10Hz, 1H); 4.39-4.37 (t, 1H), 4.29-4.11 (m; 3H), 3.84-3.82 (m, 1H); C 17h 12f 6n 5the LCMS[M+H of O] +be calculated as 416.29; Be found to be for 416.14 (residence times: 2.64min)
Example 55
Synthesizing of methyl azetidine-3-carboxylate hydrochloride
Figure BDA0000484103910001991
By azetidine-3-carboxylic acid (1g, 9.8mmol) at MeOH(10mL) in a kind of suspension be cooled to 5 ℃.Dropwise add thionyl chloride (5.83g, 49.45mmol), keep this temperature of reaction below 30 ℃.Then this mixture is heated to 65 ℃ of lasting 10-12h.This reaction mixture is under reduced pressure concentrated to produce methyl azetidine-3-carboxylate hydrochloride, for viscosity brown oil (1.3g, 90%), it is not further purified and is used.
(Z) synthesizing of-methyl 1-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-carboxylicesters
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.5g, 1.0eq.) is dissolved in to DCM(20mL) in.This reaction mixture is cooled to-60 ℃, now adds methyl azetidine-3-carboxylate hydrochloride (0.25g, 1.2eq), T3P(50% in EtOAc) (1.0mL, 1.2eq), be then DIPEA(0.48mL, 2eq.).This limpid reaction mixture is stirred to 45min at-60 ℃.This reaction mixture is being reduced pressure (25 ℃, 20mmHg), concentrate, to obtain crude product, passed through chromatography (the 2%-3% methyl alcohol in DCM) and carried out purifying to provide (Z)-methyl 1-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-carboxylicesters (0.15g, 24% productive rate).
(Z) synthesizing of-1-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-carboxylic acid
Figure BDA0000484103910002001
By (Z)-methyl 1-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-carboxylicesters (0.1g, 1.0eq.) be dissolved in methyl alcohol: in water (10mL, 1:1).Add LiOH(0.010g, 1.0eq.).This reaction mixture is at room temperature stirred to 1-2h.This reaction mixture is gone out with 10mL shrend and use rare HCl to carry out acidifying until pH=2-3.By this ethyl acetate (10mL X3) extraction for water layer.By the salt water washing of this organic layer, by dried over sodium sulfate, and under reduced pressure concentrate, to obtain (Z)-1-(3-(3-(3 of 0.060g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl) azetidine-3-carboxylic acid (62.5% productive rate). 1H?NMR(400MHz,DMSO)δ=9.38(s,1H),8.54(s,2H),8.29(s,1H),7.40-7.42(d,J=10.4Hz,1H),5.93-5.96(d,J=10.4Hz,1H),4.23-4.27(m,2H),4.12-4.16(m,3H)。C 17h 13f 6n 4o 3lCMS[M+H] +be calculated as 435.29; Be found to be for 435.14 (residence times: 2.55min).
Example 56
(Z) synthesizing of-tertiary butyl 6-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acrylamido)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.250g, 1.0eq.) is dissolved in to DCM(12mL) in.Add tertiary butyl 6-amino-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (0.17g, 1.2eq.), and this reaction mixture is cooled to-60 ℃.Then at the same temperature, add T 3p(0.51mL, 1.2eq.), then add DIPEA(0.24mL, 2.0eq.).This reaction mixture is stirred to 30min, and be transferred in water (50mL) and with DCM(2X50mL) extract.By salt solution for organic layer (50mL) washing of this merging, use anhydrous MgSO 4dry, filter and reducing pressure (25 ℃, 20mm Hg) under concentrate, to obtain crude product, passed through chromatography (0-5%MeOH in DCM) and carried out purifying to provide (Z)-tertiary butyl 6-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acrylamido)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (0.28g; 66.1% productive rate).
(Z) synthesizing of-N-(3-azabicyclic [3.1.0] hexane-6-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acrylamide hydrochloride
By (Z)-tertiary butyl 6-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acrylamido)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (0.05g, 1.0eq.) be dissolved in DCM(3mL) in, be cooled to 0 ℃, now dropwise add diox: HCl(0.2mL) and stir 30min.Allow this reaction heat to room temperature and stir 30min, under reduced pressure concentrate.This crude product and ether are ground to obtain (Z)-N-(3-azabicyclic [3.1.0] hexane-6-yl)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acrylamide hydrochloride (0.015g, 37.5% productive rate). 1h NMR (400MHz, DMSO) δ, 9.61 (s, 1H); 8.75 (s, 2H), 8.60 (s, 2H); 8.30 (s, 1H), 7.38-7.40 (d, J=10.4Hz; 1H), 5.87-5.89 (d, J=10.4Hz, 1H); 2.91 (s, 1H), 2.14 (s; 2H), 1.23 (s, 3H); Chemical formula: C 18h 16f 6n 5the LCMS[M+H of O] +be calculated as 432.34; Be found to be for 432.19 (residence times: 2.302min).
Example 57
Synthesizing of tert-butyl 6-((((9H-fluorenes-9-yl) methoxyl group) carbonyl) amino)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters
Figure BDA0000484103910002021
At 5 ℃, tert-butyl 6-amino-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (1g, 1.0eq.) is added into sodium bicarbonate (0.84g; 2.0eq.) in a kind of solution in water (5ml).Dropwise be added on FMOC-Cl(1.56g, 1.2eq. in Isosorbide-5-Nitrae-dioxs (10ml)).This reaction mixture is at room temperature stirred to 3h, be transferred in the water (50mL) of ice and with EtOAc(2x100mL) extract.By salt solution for organic layer (2x50mL) washing of these merging, use Na 2sO 4dry, filter and concentrate tert-butyl 6-((((9H-fluorenes-9-yl) methoxyl group) carbonyl) amino)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (productive rate: 90%) to obtain 1.9g under decompression (25 ℃, 20mm Hg).
(9H-fluorenes-9-yl) methyl) 3-azabicyclic [3.1.0] hexane-6-aminocarbamic acid ester synthetic
Figure BDA0000484103910002022
Tert-butyl 6-((((9H-fluorenes-9-yl) methoxyl group) carbonyl) amino)-3-azabicyclic [3.1.0] hexane-3-carboxylicesters (1.9g, 1.0eq.) is dissolved in to DCM(20mL) in.At 0 ℃, dropwise add TFA(1.38ML, 4eq.) and this reaction mixture is at room temperature stirred to 4h.This reaction mixture is cooled to 0 ℃ and by saturated NaHCO 3neutralization.The solid going out by filtration collecting precipitation is to obtain (9H-fluorenes-9-yl) methyl) 3-azabicyclic [3.1.0] hexane-6-aminocarbamic acid ester (69% productive rate).
(Z)-(9H-fluorenes-9-yl) methyl 3-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-azabicyclic [3.1.0] hexane-6-yl) carbamate synthetic
Figure BDA0000484103910002031
By (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (1.0g, 1.0eq.) be dissolved in DCM(50mL) in and be cooled to-60 ℃, now add (9H-fluorenes-9-yl) methyl) 3-azabicyclic [3.1.0] hexane-6-aminocarbamic acid ester (1.09g, 1.2eq), T3P(50% be in EtOAc) (2.02mL, 1.2eq) and DIPEA(0.95mL, 2eq.) process.This limpid reaction mixture is stirred to 1h at-60 ℃, water cancellation and extracting with DCM.By this organic layer dried over sodium sulfate, (25 ℃ of decompressions, 20mm Hg) under concentrate, to obtain crude product, passed through chromatography (2% methyl alcohol in DCM) and carried out purifying to produce (Z)-(9H-fluorenes-9-yl) methyl 3-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-azabicyclic [3.1.0] hexane-6-yl) carbamate (1.26g, 69% productive rate).
(Z) synthesizing of-1-(6-amino-3-azabicyclic [3.1.0] hexane-3-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910002041
By (Z)-(9H-fluorenes-9-yl) methyl 3-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-azabicyclic [3.1.0] hexane-6-yl) carbamate (0.3g, 1.0eq.) is dissolved in DMF(0.75ml) in.Dropwise add TEA(0.75ml) and this reaction mixture is at room temperature stirred to 4h, water (10mL) cancellation and extracting by ethyl acetate (3x50mL).By salt solution for organic layer (50mL) washing of these merging, use Na 2sO 4dry, filter and reducing pressure (25 ℃, 20mm Hg) under concentrate, to obtain the crude product of 0.2g, passed through chromatography (10% methyl alcohol in DCM) and carried out purifying to obtain (Z)-1-(6-amino-3-azabicyclic [3.1.0] hexane-3-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone (0.1g, 50% productive rate). 1h NMR (400MHz, DMSO) δ=9.10 (s, 1H); 8.49 (s, 2H), 8.30 (s; 1H), 7.30-7.32 (d, J=10Hz; 1H), 6.07-6.09 (d, J=10Hz; 1H), 3.65-3.68 (d, 1H); 3.48 (s, 1H), 3.35-3.45 (m; 1H), 3.29-3.30 (d, 1H); 2.28 (s; 1H), 1.48-1.49 (m, 2H); 1.22 (s, 1H); C 18h 16f 6n 5the LCMS[M+H of O] +be calculated as 432.34; Be found to be for 432.19 (residence times: 2.1min).
Example 58
(Z)-tert-butyl 6-(3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiro [3.4] octane-2-carboxylicesters synthetic
Figure BDA0000484103910002051
By (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.3g, 1eq.) is dissolved in ethyl acetate (20mL) and is cooled to-70 ℃, now add the tertiary butyl-2,6-diaza spiro [3.4] octane-2-carboxylicesterss (0.22g, 1.2eq), T3P(50% are in EtOAc) (0.61mL, 1.2eq), then add DIPEA(0.6mL, 4eq.).This limpid reaction mixture is stirred to 1h at-60 ℃, (25 ℃ of decompressions, 20mm Hg) under concentrate, to obtain crude product, passed through chromatography (the 3%-4% methyl alcohol in DCM) and carried out purifying to produce (Z)-tert-butyl 6-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiro [3.4] octane-2-carboxylicesters (0.2g; 43% productive rate).
(Z)-3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diaza spiro [3.4] octane-6-yl) third-2-alkene-1- ketone 2,2,2-trifluoro-acetate synthetic
Figure BDA0000484103910002052
By (Z)-tert-butyl 6-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-2,6-diaza spiro [3.4] octane-2-carboxylicesters (0.05g) is dissolved in DCM(20mL) in, be cooled to 0 ℃ and add CF 3cOOH(0.5mL).This reaction mixture is stirred to 4h at room temperature, (35 ℃ of decompressions, 20mm Hg) under concentrate to provide (Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(2,6-diaza spiro [3.4] octane-6-yl) third-2-alkene-1- ketone 2,2,2-trifluoro-acetate (0.03g, 95% productive rate). 1h NMR (400MHz, DMSO) δ=9.25 (s, 1H), 8.77 (brs; 1H), 8.59 (s, 2H), 8.30 (s; 1H), 7.39-7.37 (d, 1H, J=10.4Hz); 6.15-6.12 (d, J=10.4Hz, 1H), 3.86-3.65 (brs; 4H), 2.14 (s, 2H), 1.49 (s; 2H), 0.85-1.23 (m, 2H); C 19h 18f 6n 5the LCMS[M+H of O] +be calculated as 446.36; Be found to be for 446.12 (residence times: 2.161min).
Example 59
Figure BDA0000484103910002061
4-is chloro-3, two (trifluoromethyl) benzamide of 5-synthetic
Figure BDA0000484103910002062
By chloro-4-3, two (trifluoromethyl) cyanobenzenes (1g, 1.0eq.) of 5-are dissolved in DMSO(10mL) in.In this reaction mixture, add K 2cO 3(0.55g, 1.1eq.) and H 2o 2(1mL), and at room temperature stir 2-3h, then pour in frozen water (20mL).Collect the throw out forming by filtration, and wash to obtain the crude product (90% productive rate) of 1.0g with sherwood oil, it is not further purified and is used in next step.
4-is chloro-3, two (trifluoromethyl) benzo thioamides of 5-synthetic
By chloro-4-3, two (trifluoromethyl) benzamide (1.2g, 1.0eq.) of 5-are dissolved in toluene (20mL) and add Lao Weisen reagent (3.32g, 2.0eq.).This reaction mixture is stirred to 8h at 90 ℃, then filter.This filtrate is poured in water.By this compound EtOAc(3X100mL) extract.By salt solution for organic layer (3x50mL) washing of these merging, use Na 2sO 4dry, filter and concentrate 4-to obtain 2g chloro-3 under decompression (25 ℃, 20mmHg), 5-pair of (trifluoromethyl) benzo thioamides (95% productive rate), are not further purified it and are used in next step.
3-(4-is chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazole synthetic
Figure BDA0000484103910002071
By chloro-4-3, two (trifluoromethyl) the benzo thioamides (1g, 1.0eq.) of 5-are dissolved in DMF(10mL) in.Add hydrazine hydrate (0.32g, 2.0eq.) and this reaction mixture is at room temperature stirred to 1h.Then add formic acid (3mL) and this reaction mixture is heated to 90 ℃ and maintain 2-3h.This reaction mixture is slowly poured in saturated sodium bicarbonate solution, maintain the temperature at 25 ℃-30 ℃.By wanted product EtOAc(3X50mL) extract.By salt solution for organic layer (50mL) washing of these merging, use Na 2sO 4dry, filter and reducing pressure (25 ℃, 20mmHg), concentrate, to obtain the crude product of 1.5g, passed through chromatography (40% ethyl acetate in hexane) and carried out purifying to obtain the 3-(4-chloro-3 of 0.150g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazole (15% productive rate)
(Z)-3-(3-(4-is chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone synthetic
By 3-(4-is chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazole (0.1g, 1.0eq.) is dissolved in DMF(5mL) in.Add DABCO(0.071g, 2eq.), and stir 30min.Then adding (Z)-1-(3,3-difluoro azetidin-1-yl)-3-iodo third-2-alkene-1-ketone (0.095g, 1.1eq.) at room temperature stirs 5h by this reaction mixture and is then poured onto in the water (50mL) of ice.By product EtOAc(3X15mL) extract.By salt solution for organic layer (20mL) washing of these merging, use Na 2sO 4dry, filter and pass through (25 ℃ of rotary evaporations, 20mm Hg) concentrate, to obtain the crude product of 0.150g, it is carried out to purifying to obtain (Z)-3-(3-(4-chloro-3, two (trifluoromethyl) phenyl of 5-)-1H-1 by chromatography, 2,4-triazol-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone (0.004g, 3% productive rate). 1h NMR (400MHz, DMSO) δ=9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J=10.4Hz, 1H), 6.00-5.04 (d, J=10.4Hz, 1H), 4.55-4.58 (m, 2H), (4.33-4.36 m, 2H) C 16h 10clF 8n 4the LCMS[M+H of O] +be calculated as 461.7; Be found to be for 461.14 (residence times: 2.99min).
Example 60
(Z) synthesizing of-1-(3-(amino methyl)-3-fluorine azetidin-1-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910002081
Synthesizing of tert-butyl ((3-fluorine azetidin-3-yl) methyl) carbamate
Figure BDA0000484103910002091
Synthesizing of 1-diphenyl-methyl-3-hydroxy azetidine-3-nitrile
Figure BDA0000484103910002092
1-dibenzo-p-methyl-aza-cyclobutane-3-ketone (50g, 210mmol) is dissolved in methyl alcohol (250mL).Add KCN(15g, 316mmol at 25 ℃) and NaHSO 3(32.86g, 316mmol) and this reaction mixture is at room temperature stirred to 16h.By rare HCl acidifying for this reaction mixture, and by this for product ethyl acetate (200mL x3) extract.By the salt water washing of each organic layer, use anhydrous Na 2sO 4dry, and under reduced pressure concentrate to obtain 45.0g crude product, it is carried out to purifying by chromatography, to provide 1-diphenyl-methyl-3-hydroxy azetidine-3-nitrile (18% productive rate) of 10.5g. 1H?NMR(400MHz,CDCl 3,ppm)δ=7.5-7.2(m,10H);4.43(s,1H);3.73-3.71(d,2H);3.27-3.24(t,2H)。
Synthesizing of 1-diphenyl-methyl-3-fluorine azetidine-3-nitrile
Figure BDA0000484103910002093
1-diphenyl-methyl-3-hydroxy azetidine-3-nitrile (10.5g, 39.7mmol) is dissolved in DCM, and is cooled to-78 ℃.Slowly add DAST(12.80g, 79.45mmol) and allow this reaction mixture to heat to room temperature, now it is further stirred to 5h.Reaction mixture is cooled to 0 ℃ and be transferred to 500mL NaHCO 3in solution, and extract with (100mL x3) DCM.By the organic layer salt water washing merging, use Na 2sO 4dry, and under reduced pressure concentrate to obtain 15.0g crude product, it is carried out to purifying by chromatography, to obtain 1-diphenyl-methyl-3-fluorine azetidine-3-nitrile of 6.0g.(57.14% productive rate). 1H?NMR(400MHz,CDCl 3,ppm)δ=7.6-7.1(m,10H);4.46(s,1H);3.9-3.6(m,2H);3.5-3.2(m,2H)。
Synthesizing of (1-diphenyl-methyl-3-fluorine azetidin-3-yl) methylamine
Figure BDA0000484103910002101
1-diphenyl-methyl-3-fluorine azetidine-3-nitrile (0.5g, 1.88mmol) is dissolved in methyl alcohol (25mL).Add NaBH at 0 ℃ 4(0.49g, 13.14mmol) and NiCl 2(0.044g, 0.34mmol) and this reaction mixture is at room temperature stirred to 14h.These solid by filtration that form are removed and this filtrate is under reduced pressure concentrated.This crude product is carried out to purifying to provide (1-diphenyl-methyl-3-fluorine azetidin-3-yl) methylamine (30% productive rate) of 0.15g by chromatography (0-5% methyl alcohol-DCM). 1H?NMR(400MHz,CDCl 3,ppm)δ=7.46-7.19(m,10H);4.48(s,1H);3.38-3.34(t,2H);3.26-3.09(m,4H)。
Synthesizing of the tertiary butyl-(1-diphenyl-methyl-3-fluorine azetidin-3-yl) methyl carbamate:
Figure BDA0000484103910002102
(1-diphenyl-methyl-3-fluorine azetidin-3-yl) methylamine (0.5g, 1.85mmol) is dissolved in to DCM(20mL) in and 0 ℃ add Boc acid anhydrides (0.20g, 0.924mmol).Allow this reaction mixture to heat to room temperature, now stirred 4h.This reaction mixture is under reduced pressure concentrated to the tertiary butyl (1-diphenyl-methyl-3-fluorine azetidin-3-yl) methyl carbamate (100% productive rate) to obtain 0.5g. 1H?NMR(400MHz,CDCl 3,ppm)δ=7.44-7.19(m,10H);5.32(s,1H);4.84(s,1H);3.69-3.61(m,2H);3.38-3.033(m,2H);3.18-3.10(m,2H)。
Synthesizing of tert-butyl (3-fluorine azetidin-3-yl) methyl carbamate
Figure BDA0000484103910002111
Tert-butyl (1-diphenyl-methyl-3-fluorine azetidin-3-yl) methyl carbamate (0.6g, 1.35mmol) is dissolved in ethanol and adds Pd (OH) 2(0.38gm, 2.7mmol).At H 2under, this reaction mixture is at room temperature stirred to 14h.These solid by filtration are removed and this filtrate is under reduced pressure concentrated to tert-butyl (the 3-fluorine azetidin-3-yl) methyl carbamate (66% productive rate) to obtain 0.2g.
(Z)-tert-butyl 1-(3-(3-(3,5-two (trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidin-3-yl) methyl carbamate synthetic
Figure BDA0000484103910002112
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.20g, 0.56mmol) is dissolved in to DCM(10mL) in.This reaction mixture is cooled to-60 ℃, at this temperature, adds tert-butyl (3-fluorine azetidin-3-yl) methyl carbamate (0.127g, 0.62mmol), then add T 3p(50% is in EtOAc) (0.434g, 0.67mmol).Then slowly introduce DIPEA(0.144g, 1.11mmol).This limpid reaction mixture is stirred to an other 45min at-60 ℃.This reaction mixture is under reduced pressure concentrated, to obtain crude product, passed through column chromatography (0-15% ethyl acetate-hexane) and carried out purifying to obtain (Z)-tert-butyl (1-(3-(3-(3 of 150mg, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidin-3-yl) methyl carbamate (productive rate 50%). 1H?NMR(400MHz,CDCl 3,ppm)δ=9.7(s,1H);8.63(s,2H);7.94(s,1H);7.24-7.21(d,J=10.8Hz,1H);5.67-5.64(d,J=10.8,1H);4.41-4.16(m,4H);3.76-3.54(m,3H)。
(Z) synthesizing of-1-(3-(amino methyl)-3-fluorine azetidin-1-yl)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910002121
By (Z)-tert-butyl (1-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidin-3-yl) methyl carbamate (0.15g, 0.279mmol) be dissolved in DCM(10mL) in, and add TFA(0.1mL at 0 ℃).This reaction mixture is at room temperature stirred to 4h and under reduced pressure concentrates, to obtain the crude product of 0.5g, passed through chromatography (0-5% methyl alcohol in DCM) and carried out purifying to obtain (Z)-1-(3-(amino methyl)-3-fluorine azetidin-1-yl)-3-(3-(3 of 15mg, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) third-2-alkene-1-ketone (productive rate 15%). 1H?NMR(400MHz,CDCl 3,ppm)δ=9.4(s,1H);8.54(s,2H);8.32(s,1H);8.13(s,3H);7.49-7.46(d,J=10Hz,1H);6.0-5.97(d,J=10Hz,1H);4.41-4.06(m,4H);3.49-3.36(m,3H)。C 17h 15f 7n 5the LCMS[M+H of O] +be calculated as 438.3; Be found to be for 438.19 (residence times: 2.298min).
Example 61
The synthetic schemes of methyl 3-fluorine azetidine-3-carboxylate hydrochloride
Figure BDA0000484103910002131
Synthesizing of 1-diphenyl-methyl-3-fluorine azetidine-3-carboxylic acid
Figure BDA0000484103910002132
1-diphenyl-methyl-3-fluorine azetidine-3-nitrile (3.5g, 1.0eq.) is dissolved in ethanol and adds the NaOH aqueous solution (1N).By this reaction mixture refluxed 5h, then allow it to be cooled to room temperature, at this temperature, used rare HCl acidifying (pH～3), and extracted by ethyl acetate (50mL x3).By the salt water washing of the organic layer of these merging, by dried over sodium sulfate, and under reduced pressure concentrate, to obtain 1-diphenyl-methyl-3-fluorine azetidine-3-carboxylic acid (13% productive rate) of 0.5g.This product is not further purified and is used in next step.
Synthesizing of 3-fluorine azetidine-3-carboxylic acid hydrochloride
Figure BDA0000484103910002133
1-diphenyl-methyl-3-fluorine azetidine-3-carboxylic acid (0.5g, 1.0eq.) is dissolved in ethanol.Add Pd (OH) 2(0.5g) and by this reaction mixture in room temperature at H 2under atmosphere, stir 14h.These solid by filtration are removed and this filtrate is under reduced pressure concentrated to the 3-fluorine azetidine-3-carboxylic acid hydrochloride (30% productive rate) to obtain 150mg.This product is not further purified and is used in next step.
Synthesizing of methyl 3-fluorine azetidine-3-carboxylate hydrochloride
Figure BDA0000484103910002141
3-fluorine azetidine-3-carboxylic acid hydrochloride (0.10g, 8.4mmol) is dissolved in methyl alcohol (2mL), and is cooled to 5 ℃.Dropwise add thionyl chloride (0.05g, 4.2mmol).This reaction mixture also is under reduced pressure concentrated to provide methyl 3-fluorine azetidine-3-carboxylate hydrochloride 65 ℃ of heated overnight.This product is not further purified and is used in next step.
(Z) synthesizing of-methyl 1-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidine-3-carboxylicesters
Figure BDA0000484103910002142
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.20g, 1.0eq.) is dissolved in to DCM(4mL) in.This reaction mixture is cooled to-60 ℃, at this temperature, adds methyl 3-fluorine azetidine-3-carboxylate hydrochloride (0.09g, 1.2eq) and T3P(50% in EtOAc) (0.427g, 1.2eq), then add DIPEA(0.146g, 2eq.).This limpid reaction mixture is stirred to 45min at-60 ℃, (25 ℃ of decompressions, 20mmHg), concentrate, to obtain crude product, passed through chromatography (20%-30% ethyl acetate in hexane) and carried out purifying to provide (Z)-methyl isophthalic acid-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidine-3-carboxylicesters.(40mg; 24% productive rate). 1HNMR(400MHz,CDCL3)δ9.51(S,1H),8.62(s,2H),7.96(s,1H),7.20-7.18(d,J=10.8,1H),5.70-5.68(d,J=10.8Hz,1H),4.15-3.82(m,4H),3.82(s,3H)。
Example 62
(Z) synthesizing of-1-(3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidine-3-carboxylic acid
Figure BDA0000484103910002151
By (Z)-methyl 1-(3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidine-3-carboxylicesters (0.01g, 1.0eq.) be dissolved in methyl alcohol: water (0.2mL, 1:1) and add LiOH(1.0mg, 1.0eq).This reaction mixture is at room temperature stirred to 2h.This reaction mixture is gone out with 10mL shrend and use rare HCl to be acidified to pH2-3.By this ethyl acetate (10mL x3) extraction for water layer.Then by the salt water washing of the organic layer of these merging, by dried over sodium sulfate, and under reduced pressure concentrate, to obtain (Z)-1-(3-(3-(3 of 0.002g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) acryloyl)-3-fluorine azetidine-3-carboxylic acid.Productive rate (20.83%). 1H?NMR(400MHz,CDCL3)δ8.92(S,1H),8.54(s,2H),8.29(s,1H),7.45-7.42(d,J=10.4,1H),6.00-5.98(d,J=10.4Hz,1H),3.73(m,4H)。
Example 63
Figure BDA0000484103910002152
1-(1-diphenyl-methyl-3-fluorine azetidin-3-yl)-N, N-dimethyl methylamine synthetic
(1-diphenyl-methyl-3-fluorine azetidin-3-yl) methylamine (0.5g, 1.0eq.) is dissolved in methyl alcohol, and adds HCHO(0.138g, 2.5eq. at 0 ℃) and NaCNBH 3(0.47g, 4.0eq.).By this reaction mixture at stirring at room temperature 14h, then use ammonium chloride solution cancellation and extracting with DCM.By the salt water washing of this organic layer, by dried over sodium sulfate, and under reduced pressure concentrate, to obtain 1-(1-diphenyl-methyl-3-fluorine azetidin-3-yl)-N of 150mg, N-dimethyl methylamine (100%), is not further purified it and is used in next step.
1-(3-fluorine azetidin-3-yl)-N, N-dimethyl methylamine synthetic
Figure BDA0000484103910002162
By 1-(1-diphenyl-methyl-3-fluorine azetidin-3-yl)-N, N-dimethyl methylamine (0.6g, 1.0eq.) is dissolved in ethanol.Add Pd (OH) 2(0.6g).At H 2under atmosphere by this reaction mixture at stirring at room temperature 14h.These solid by filtration are removed, this filtrate is under reduced pressure concentrated, to obtain 1-(3-fluorine azetidin-3-yl)-N of 300mg, N-dimethyl methylamine (68% productive rate), is not further purified it and is used in next step.
(Z)-3-(3-(3, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino) methyl)-3-fluorine azetidin-1-yl) third-2-alkene-1-ketone synthetic
Figure BDA0000484103910002171
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.50g, 1.0eq.) is dissolved in to DCM(10mL) in.This reaction mixture is cooled to-60 ℃, at this temperature, adds 1-(3-fluorine azetidin-3-yl)-N, N-dimethyl methylamine (0.22g, 1.2eq) and T3P(50% are in EtOAc) (1.08g, 1.2eq), then add DIPEA(0.36g, 2eq.).This limpid reaction mixture is stirred to 45min at-60 ℃.This reaction mixture is being reduced pressure (25 ℃, 20mmHg), concentrate, to obtain crude product, it is carried out to purifying to provide (Z)-3-(3-(3 of 12mg by chromatography, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(3-((dimethylamino) methyl)-3-fluorine azetidin-1-yl) third-2-alkene-1-ketone (3% productive rate). 1h NMR (400MHz, CDCl 3) δ=9.75 (s, 1H), 8.62 (s, 2H); 7.94 (s, 1H), 7.24-7.21 (d, J=10.8Hz; 1H), 5.69-5.66 (d, J=10.8Hz, 1H); 4.37-4.25 (m, 2H), 4.22-4.15 (m; 2H), 2.82-2.76 (d, 2H); (2.35 s, 2.35,1H); C 19h 19f 7n 5the LCMS[M+H of O] +be 466.4; Be found to be for 466.3 (residence times: 2.263min)
Example 64
Figure BDA0000484103910002172
Under nitrogen atmosphere, in a 25-mL sealed tube that is equipped with partition, add THF(5mL) and sodium hydride (0.08g, 2.02mmol).This reaction mixture is cooled to 0 ℃, and portions interpolation 4-(two (trifluoromethyl) phenyl of 3,5-) pyrrolidin-2-one (0.3g, 1.01mmol), the temperature lower than 0 ℃ maintained.By this reaction mixture refluxed 3.5h, and be cooled to afterwards-10 ℃.In this reaction mixture, dropwise add (Z)-sec.-propyl 3-iodo acrylate (0.33g, 1.21mmol).Reaction mixture is further stirred to another 30min at-10 ℃.This reaction mixture is transferred in water (50mL) and with EtOAc(2x50mL) extract.By saturated brine solution for organic layer (50mL) washing of these merging, use anhydrous Na 2sO 4dry, filter, and under reduced pressure concentrate, to obtain crude compound.This roughage is passed through to column chromatography (silicon 60/120, EtOAc-hexane gradient) carry out purifying, and again use 60%EtOAc-hexane to carry out purifying to provide 0.015g (Z)-4-(3 as moving phase by preparative TLC, two (trifluoromethyl) phenyl of 5-)-1-(3-(3,3-difluoro azetidin-1-yl)-3-oxygen third-1-thiazolinyl) pyrrolidin-2-one (productive rate 3.3%). 1h NMR (400MHz, CDCl 3) δ, 7.83 (s, 1H); 7.73 (s, 2H); (7.16-7.19 d, J=10.4Hz, 1H); (5.08-5.11 d, J=10.4Hz, 1H); 4.43-4.51 (m, 3H); (4.30-4.36 t, J=12Hz, 2H); 3.96-4.01 (m, 1H); 3.75-3.79 (m, 1H); 2.95-3.02 (m, 1H); 2.68-2.75 (m, 1H); C 18h 15f 8n 2o 2lCMS[M+1] +be 442.3, discovery is that 443.14(is at RT2.932min).
Example 65
(Z) synthesizing of-3-(2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910002181
2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles's is synthetic:
Figure BDA0000484103910002191
At room temperature, by pyrroles (5.15g, 76.79mmol) at THF(120mL) in a kind of solution pack in a 500mL3 neck round-bottomed flask and be cooled to 0 ℃.Drip portions and add NaH(2.21g, 92.12mmol) and this reaction mixture is stirred to 1h at 0 ℃.In this reaction mixture, add ZnCl 2(10.4g, 77mmol), and stir 1h at 0 ℃.Add 1-bromo-3, two (trifluoromethyl) benzene (5.0g, 17.0mmol) of 5-also will react degasification 10min, and add palladium diacetate (0.172g, 0.76mmol) and 2-(dicyclohexylphosphontetrafluoroborate) phenylbenzene (0.269g, 0.76mmol), and will react backflow 48h.Reaction mixture is transferred in water (100mL) and uses EtOAc(3x300mL) extract and by saturated brine solution for organic layer (3x150mL) washing of this merging, use MgSO 4dry, filter rough 2-(two (trifluoromethyl) phenyl of 3, the 5-)-1H-pyrroles who also under reduced pressure concentrates to provide 7g, it is carried out to purifying to provide the pure products of 0.8g by chromatography.C 12h 6f 6the LCMS[M-H of N] -be calculated as 278.18; Be found to be 278.19 (residence time 3.383min)
(Z) synthesizing of-sec.-propyl 3-(2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles-1-yl) acrylate:
Figure BDA0000484103910002192
By 2-(3,5-two (trifluoromethyl) phenyl)-1H-pyrroles (1) (0.7g, 2.50mmol) at DCM(14mL) in a kind of solution pack in a 100mL3 neck round-bottomed flask and by reaction mixture and be cooled to 0 ℃.Add TEA(0.379g, 3.76mmol at 0 ℃ simultaneously) and isopropylacrylic acid ester (0.421g, 3.76mmol) and stirring 1.5h.Reaction mixture is transferred in water (50mL) and uses EtOAc(3x20mL) extract and by saturated brine solution for organic layer (3x50mL) washing of this merging, use MgSO 4dry, filter and under reduced pressure concentrate to provide the crude compound of 1.5g, it is carried out to purifying to obtain (Z)-sec.-propyl 3-(2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles-1-yl) acrylate (productive rate 15%) of 0.150g by column chromatography. 1h NMR (400MHz, CDCl 3, ppm) and δ=1.279-1.318 (m, 6H); 5.106 (m, 1H); (5.521-545 d, J=9.6Hz, 1H); (6.377 s, 1H); (6.494 s, 1H); (6.643-6.763 d, J=10Hz, 1H); (7.800-7.831 m, 3H): C 18h 16f 6nO 2lCMS[M+H] +be calculated as 392.31; Be found to be 392.4 (residence time 3.820min).
(Z) synthesizing of-3-(2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles-1-yl) vinylformic acid (3):
Figure BDA0000484103910002201
By (Z)-sec.-propyl 3-(2-(3, two (trifluoromethyl) phenyl of 5-)-1H-pyrroles-1-yl) acrylate (0.15g, 0.383mmol) at THF(10mL) and water (10mL) in a kind of solution pack in a 100mL3 neck round-bottomed flask, and at room temperature stir.In this reaction mixture, add LiOH.H 2o(0.027g, 1.15mmol), and will react and further stir 16h.Reaction mixture is carried out to acidifying by rare HCl and with EtOAc(3x20mL) extract.By salt brine solution for organic layer (3x50mL) washing of these merging, use MgSO 4dry, filter, and under reduced pressure concentrate, to obtain (Z)-3-(2-(3 of 0.15g, two (trifluoromethyl) phenyl of 5-)-1H-pyrroles-1-yl) vinylformic acid (3) (productive rate: 88%), use it for next step and do not carry out purifying.C 15h 10f 6nO 2lCMS[M+H] +be calculated as 350.23; Be found to be 350.39 (residence time 3.129min).
(Z) synthesizing of-3-(2-(two (trifluoromethyl) phenyl of 3,5-)-1H-pyrroles-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone:
Figure BDA0000484103910002202
By (Z)-3-(2-(3, two (trifluoromethyl) phenyl of 5-)-1H-pyrroles-1-yl) vinylformic acid (0.15g, 0.429mmol) at DCM(10mL) in a kind of solution pack in a 100mL3 neck round-bottomed flask, and be cooled to 0 ℃, and dropwise add 3,3-difluoro azetidine hydrochloride (0.052g, 0.558mmol).Dropwise add T3P(50% in EtOAc) (0.163g, 0.514mmol), then add DIPEA(0.11g, 0.858mmol) and this reaction mixture is stirred to 1h at 0 ℃.This reaction mixture is under reduced pressure concentrated, to obtain 0.2g crude product, passed through column chromatography (60/120 silica gel, 0-3% ethyl acetate: n-hexane gradient) carry out purifying to obtain (Z)-3-(2-(3 of 0.01g, two (trifluoromethyl) phenyl of 5-)-1H-pyrroles-1-yl)-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone (productive rate 6.6%). 1H?NMR(400MHz,CDCl 3,ppm)δ=4.307-4.425(m,4H);5.523-5.443(d,J=10Hz,1H);6.387-6.404(t,1H);6.500-6.509(t,1H);6.765-6.790(d,J=10Hz,1H);7.704-7.715(t,1H);7.811-7.845(m,3H)。C 18h 13f 8n 2the LCMS[M+H of O] +be calculated as 435.29; Be found to be for 425.49 (residence times: 3.292min).
Example 66
(Z) synthesizing of-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl)-1-(4-hydroxy piperidine-1-yl) third-2-alkene-1-ketone
Figure BDA0000484103910002211
(Z)-3-(3-(two (trifluoromethyl) phenyl of 3,5-)-1H-1,2,4-triazol-1-yl) vinylformic acid (0.20g, 1.0eq.) is dissolved in to DCM(10mL) in.Add piperidines-4-alcohol (0.07g, 1.2eq.) and this reaction mixture is cooled to-60 ℃.Add T 3p(propyl group phosphoric anhydride) (0.40mL, 1.2eq) and DIPEA(0.19mL, 2.0eq.).Reaction mixture is stirred to 30min.Then this reaction mixture is transferred in water (50mL) and with DCM(2X50mL) extract.By salt solution for organic layer (50mL) washing of these merging, use anhydrous MgSO 4dry, filter and reducing pressure (25 ℃, 20mmHg), concentrate, to obtain crude product, passed through chromatography (0-3%MeOH in DCM) and carried out purifying to obtain (Z)-3-(3-(3 of 0.025g, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl)-1-(4-hydroxy piperidine-1-yl) third-2-alkene-1-ketone (productive rate: 10%). 1h NMR (400MHz, CDCl 3) δ, 8.75 (s, 1H), 8.58 (s; 2H), 7.93 (s, 1H); (7.08-7.11 d, J=10.4Hz, 1H); (6.01-6.04 d, J=10.4Hz, 1H); (4.02-4.14 m, 1H), 3.98-4.01 (m; 1H), 3.78-3.85 (m, 1H); (3.47-3.52 s, 1H), 3.32-3.38 (s; 1H), 1.96 (s, 1H); (1.83 s, 1H), 1.27 (s; 1H), 0.90 (s, 1H); Chemical formula: C 18h 17f 6n 4o 2lCMS[M+H] +be 435.34, discovery is that 435.24(is at RT2.408min).
The inhibition of core output
In measuring, RevGFP assesses the ability that these exemplary compounds of the present invention suppress the core output of CRM1 mediation.Rev is that one comprises a kind of nuclear export signal (NES) and comprises a kind of nuclear localization signal (NLS) in its N-end structure territory from human immunodeficiency virus I's (HIV-1) albumen and in its C-end structure territory.The core output of Rev albumen depends on the people such as classical NES/CRM1 approach (Neville(Neville), 1997).The core that can observe Rev in the cell of processing through the specific inhibitor (such as LMB) of CRM1 accumulates people such as (Kau(examine), 2003).
In this mensuration, before this experiment same day, U2OS-RevGFP cell is inoculated on clear bottom, black, 384 orifice plates.In a kind of 384 orifice plates that separate, in DMEM, continuously compound is carried out to 1:2 dilution, since 40 μ M, and then transfer in these cells.Before fixing with 3.7% formaldehyde and carrying out nucleus dyeing with Hoechst33258, these cells and compound are hatched to about 1hr.GFP amount in measurement nucleus and the IC of definite every kind of compound 50people such as (Kau(examine), 2003).If compound of the present invention has an IC lower than about 10 μ M 50, they are considered to have activity in above-mentioned RevGFP measures, and most preferred compound has an IC lower than about 1 μ M 50.The result that this RevGFP measures has been shown in table 3.
Cell proliferating determining
By CellTiter
Figure BDA0000484103910002221
aQueous One Solution cell proliferating determining (Pu Luomaige company (Promega)) on MM.1S multiple myeloma cell line to study cytotoxin and the cell rejection characteristic of these compounds.This mensuration is based on a kind of electron coupling reagent PES(azophenlyene sulfovinate) existence under the cutting of tetrazolium salts, MTS.This MTS tetrazole compound is reduced to a kind of coloured formazan product by cell biological, and this product is soluble in tissue culture medium (TCM).This conversion supposition is that the NADPH or the NADH that are produced by the desaturase enzyme having in metabolic activity cell complete.Measure by following enforcement: directly in culture hole, add CellTiter in a small amount
Figure BDA0000484103910002231
aQueous One solution reagent, hatches 1-4 hour, and then reads plate instrument and record the absorbancy of 490nm with 96 holes.Absorbancy shows directly relevant with their metabolic activity to cell number.
With the every hole 5x10 of 96 orifice plate 3to 1.5x10 4cell (depending on cell type) is inoculated in these cells in 100 μ L fresh cultures, and allows attached cell to adhere to spend the night.The mother liquor of these compounds is diluted to obtain eight kinds of concentration of each medicine in cell culture medium, scope is from 1nM to 30 μ M, and the DMSO that use is less than 1%v/v is as a negative control.Gained drug solution is transferred on these cells.Processing after 72h, to the CellTiter that adds 20 μ l in every hole of this 96 hole assay plate aqueous reagent, and at 37 ℃ at moistening 5%CO 2in atmosphere, this plate is hatched to 1-4 hour.Then use 96 holes to read plate instrument and record the absorbancy in every hole at 490nm.As a rule, this mensuration is carried out with three parts and these results are rendered as half maximum inhibition concentration (IC50).Optical density(OD) comparison compound concentration is drawn, and use Nonlinear regression equation (IDBS XLfit) to analyze, and calculate the IC of every kind of compound 50.
Pharmacokinetics (PK) is measured and brain: blood plasma ratio is determined
Pharmacokinetics (PK) is played the part of more and more important role in drug discovery and exploitation.Pharmacokinetics is the quantitative examination of drug absorption, distribution, metabolism and/or excretion time-histories.In the time giving a kind of medicine, it gives blood circulation that site is promptly distributed to whole body from it.A measurement of the scope of the distribution of therapeutical agent is an area under plasma concentration-time curve (AUC), is calculated to the concentration (AUC of last measurement t) and infer to infinitely great (AUC inf).Therefore AUC is a useful tolerance to quantizing drug exposure.
Generally, a kind of exposure of therapeutical agent is higher, and the impact of this agent is larger.But a kind of height of therapeutical agent exposes and can have deleterious effect to some tissue as brain.As blood brain-barrier (BBB), a kind of by the catch net closely connecting to form between endotheliocyte, when restriction wetting ability and/or macromolecular diffusion, the medicine with high AUC still can permeate this BBB and/or celiolymph.The infiltration of this class can cause undesired side effect.Current drug discovery working portion is a kind of balance for example, minimizing in order to break maximization drug exposure (AUC) between brain infiltration.
Brain and blood plasma (B:P) ratio be a kind of quantize therapeutical agent at cerebral tissue the method for the relative distribution in the recycle system, and provide like this one indication of the brain infiltration to given therapeutical agent.When for disease while being arranged in central nervous system (CNS) (comprising brain and celiolymph), high brain and blood plasma ratio are preferred.But, be preferred generally for lower brain of non-CNS therapeutical agent and blood plasma ratio, permeate and avoid potential in the caused side effect of undesired accumulation in brain and CNS organize of this therapeutical agent to minimize brain.
AUC. from mouse (N=3), gather blood to contribute whole 10 time points (before administration, 5min, 15min after administration, 30min, 1hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours).In fundamental principle in turn, mouse is bled, every mouse is to 3 time points of blood collection contribution.On point in time point, anesthetized animal under isoflurane, and through after eye socket puncture about 110 μ L blood collections of each time point are arrived to the K2EDTA(dispersion stabilizer of precooling) in pipe.By blood sample be placed into wet on ice also centrifugal (2000g, 4 ℃ at 5min) to obtain blood plasma at sample collecting in 30 minutes.By all samples freezer storage approximately at-80 ℃ until analyze.Before analyzing, sample is mixed in acetonitrile with interior mark (dexamethasone), vortex, centrifugal, and inject supernatant liquor for analyzing.(API4000, has triple level Four (Triple Quadruple) of electrospray ionization to use LC-MS-MS detecting instrument; Sensitivity superelevation liquid-phase chromatographic column C18(Acuity Ultra Performance Liquid Chromatography C18), with MeOH and formic acid as organic solvent) determine the concentration of compound in blood plasma.Use WinNonlin professional version 6.2 software packages, non-compartment pharmacokinetics model NCA200 calculates AUC value.
Brain and blood plasma (B:P) ratio.Give mouse (N=3) administration (PO is at 10mg/kg) of a group of the separating and (T of 2 hours after administration of estimation in maximal plasma concentration then maxadministration) put to death the now blood plasma of acquisition time terminal and cerebral tissue.After collection, cerebral tissue is rinsed with cool brine, dry on filter paper, weigh and on dry ice, carry out urgency and freeze by being placed on.By all samples freezer storage approximately at-80 ℃ until analyze.In the time analyzing, homogenizing, (solution PBS homogenizes, pH7.4) cerebral tissue, mix in acetonitrile with interior mark (dexamethasone), vortex, centrifugal, and inject the analysis of supernatant liquor for compound concentration, this analysis is to use LC-MS-MS method (API4000, has triple level Four (Triple Quadruple) of electrospray ionization; Sensitivity superelevation liquid-phase chromatographic column C18(Acuity Ultra Performance Liquid Chromatography column C18), use MeOH and formic acid as organic solvent).Process plasma sample by same procedure (except homogenization step), and calculate the concentration of the compound in every kind of matrix based on the typical curve producing.These results that PK measures and B:P ratio is determined are presented in table 3.
Table 3. is about the measurement result (A=<1M of exemplary compounds of the present invention; B=1-10M; C=>10M; NT=does not detect).
Figure BDA0000484103910002251
Figure BDA0000484103910002261
Figure BDA0000484103910002271
Figure BDA0000484103910002281
Figure BDA0000484103910002291
Figure BDA0000484103910002301
Figure BDA0000484103910002311
Figure BDA0000484103910002321
Figure BDA0000484103910002331
Figure BDA0000484103910002341
Figure BDA0000484103910002351
Figure BDA0000484103910002371
^ tests at 5mpk.
In the heteroplastic body of HCT-116, suppress
In the trailing flank with HCT-116 clone, and make this HCT-116 heterograft grow to about 150mm mouse inoculation 3, now start and process.Each treatment group is as follows:
Vehicle SC;
50mg/kg5-FU IP, 1-3 days;
25mg/kg compound 1 compound Q D x5SC(low dosage);
75mg/kg compound 1 compound Q D x5SC(high dosage).
Fig. 1 is the figure of gross tumor volume (as the per-cent of initial stage gross tumor volume) comparison time, and shows and suppressed tumor growth with the processing of compound 1, and demonstration superior antitumous effect compared with 5-FU.At low dosage and high dosage, compound 1 compound is all well tolerable.The apoptosis of p21, p53 induction and HCT-116 cell
HCT-116 cell is hatched 24 hours with 10 μ M compounds 1, at this moment these cells fixed and used antibody or DNA staining agent DAPI to p21 or p53 to dye.The analysis subsequently of being undertaken by immunofluorescence shows that p21 and p53 are concentrated in the core in the cell of processing with compound 1, and only use cell that vehicle (DMSO) processes tenuigenin and with core in only comprise low-level p53 and p21.
This experiment shows that compound 1 suppresses the core output function of CRM1, changes the Subcellular Localization of tumor suppressor gene albumen p53 and cell cycle protein dependent kinase inhibitor p21.
HCT-116 cell is hatched to 2,4,6,16 or 24 hours (in Fig. 2 A and 2B, point out as " 2+ ", 4+ " etc.) with 10 μ M compounds 1; or hatch 22 hours with 10 μ M compounds 1, and hatch another 2 hours (in Fig. 2 A and 2B, pointing out as " 22+2+ ") with 1 other μ M compound 1.In the time that incubation period finishes, prepare total protein extract.In addition, from hatch the cell of 2 and 24 hours with vehicle (DMSO), prepare albuminous cell extract (pointing out as "-") in Fig. 2 A and 2B.By cytoplasm protein separate with nuclear protein, carry out immunoblotting and with to p53, p21, total length (FL) PARP, the PARP of cracking and the antibody response of lamin B.
Fig. 2 A and 2B are the images of the western blotting that obtains from this test and show p21 and the p53 in compound 1 inducing cell matter part and core part.In the core part of the cell of processing with compound 1, observe the strong especially induction to p53.In addition, after Fig. 2 A and 2B are presented at 24 hours, compound 1 is induced the apoptosis of HCT-116 cell, as by PARP(apoptosis mark) minimizing and the increase of the PARP of cracking show.The PARP of cracking indicates that necrocytosis starts after hatching 16hr, and lamin is to be a loading contrast about a kind of mark of nuclear protein and Actin muscle.
PRb in HCT-116 cell appraises and decides the induction of position and phosphorylation
HCT-116 cell is hatched 24 hours with 10 μ M compounds 1, at this moment these cells fixed and used antibody or DAPI to pRb to dye.The analysis subsequently of being undertaken by immunofluorescence shows the position of appraising and deciding with the processing induced tumor suppressor gene albumen pRb of compound 1.
HCT-116 cell is hatched to 2,4,6,16 or 24 hours (in Fig. 3 A and 3B, point out as " 2+ ", 4+ " etc.) with 10 μ M compounds 1; or hatch 22 hours with 10 μ M compounds 1, and hatch another 2 hours (in Fig. 3 A and 3B, pointing out as " 22+2+ ") with 1 other μ M compound 1.In the time that the incubation period finishes, prepare total protein extract.In addition, from hatch the cell of 2 and 24 hours with vehicle (DMSO), prepare albuminous cell extract (pointing out as "-") in Fig. 3 A and 3B.By cytoplasm protein separate with nuclear protein, carry out immunoblotting and with pRb(pRb to phosphorylation phos), the antibody of pRb, Actin muscle and lamin B reacts.
Fig. 3 A and 3B are the images of the western blotting that obtains from this test and are presented at and process the loss more than the band on the top of higher levels of pRb and pRb albumen in the sample center part of 6 hours with compound 1.The pRb band on top corresponding albumen non-activity, phosphorylation, and the band correspondence of bottom unphosphorylated, the activated form of the albumen of inducing cell Cycle Arrest.Fig. 3 A and 3B show the dephosphorylation of the pRb in compound 1 inducing cell matter part and core part.
APC in HCT-116 cell and I κ B appraise and decide the induction of position
HCT-116 cell is hatched 24 hours with 10 μ M compounds 1, at this moment these cells fixed and used antibody or the DAPI of APC or I κ B are dyeed.The analysis subsequently of being undertaken by immunofluorescence show with the processing of compound 1 induce tumor suppressor protein APC and I κ B in HCT-116 cell separately appraise and decide position.Only show APC and I κ B clearly cytoplasmic (dyeing of ring sample) with the cell of vehicle treated.
Experimental autoimmunization encephalomyelitis (EAE) model
This EAE model is as the received model of multiple sclerosis for research mankind CNS demyelinating disease.Model described herein uses large female C57BL/6 or CD40 of 5-8 week -/ -mouse (13-16 week large BM gomphosis mouse) is used in this mouse the CFA(complete Freund's adjuvant (Complete Freund ' s Adjuvant) of the mycobacterium tuberculosis (DIFCO) that is supplemented with 500g) in the MOG35-55 peptide (the peptide 35-55 of myelin oligodendrocyte glycoprotein) of 200g of emulsification carry out subcutaneous inoculation.Make this mouse in the time of immunity and after 48h, accept the intraperitoneal injection of the Toxins, pertussis of 250ng (aldrich company of Sigma (Sigma-Aldrich)) with the perviousness of increase hemato encephalic barrier.After 7 days, make this mouse accept an identical booster immunization without the MOG/CFA of Toxins, pertussis.Between the 13rd day and the 18th day after immunity, clinical disease starts.In the time that representing the hind leg of soft vertical tail and weakness, all mouse start to give compound 1.This experimental design as described below and all dosed administrations be all to carry out with a kind of blind method.
This research forms by 3 groups: (i) vehicle treated; (ii) compound 1 of 25mg/kg; And (iii) 75mg/kg compound 1(per os is raised by force, 3 days-Monday, Wednesday, Friday weekly).Every group has 16-18 animal and mark look.By two independently investigator record body weight and illness and clinical score every day.Clinical scoring carried out four times to this mouse weekly, as follows: 0, there is no the detected symptom of EAE; 0.5, tail end is soft to hang down; 1, full tail is soft to hang down; 1.5, afterbody is soft to hang down and hind leg weakness; 2, acroparalysia after one-sided part; 2.5, acroparalysia after two side portions; 3, both sides hind leg complete paralysis; 3.5, both sides hind leg complete paralysis and one-sided front acroparalysia; 4, forelimb and hind leg are all benumbed (by the execution of score >4); 5, death.In experimentation, provide soft and delicious food as gelatin and Nutrical(assistant doctor high).
Fig. 4 A is the figure as the EAE score of the function of time, and has shown in such scheme for 25mg/kg(low dosage) and 75mg/kg(high dosage) group, give compound 1 and reduced clinical score in significant mode statistically.Fig. 4 B is the figure as the body weight of the function of time, and has shown that in such scheme, giving compound 1 does not affect body weight significantly.
At the 26th day, the mouse of a subgroup is put to death and use standard method that immunocyte is stood to fluorescence-activated cell sorting (FACS).Fig. 5 shows the result of FACS test, and it shows the appropriate minimizing of the quantity of the splenocyte that is associated with the compound 1 of high dosage and circulation cd8 cell.
Compound 1 and example 1 are that use at this interchangeably and refer to (Z)-3-(3-(3 that has chemical name, two (trifluoromethyl) phenyl of 5-)-1H-1,2,4-triazol-1-yl) compound 1 of table 2 of-1-(3,3-difluoro azetidin-1-yl) third-2-alkene-1-ketone.
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The relevant content of teaching of all patents, disclosed application and reference is all carried out combination by it by reference in full.
Although the present invention has carried out concrete demonstration and description with reference to its exemplary embodiment, those skilled in the art should be understood that, not departing under the scope of the present invention included by appended claims, can be made at therein the multiple change of form and details aspect.

Claims (31)

1. one kind has the compound of Formula I:
Figure FDA0000484103900000011
Or its a kind of pharmacy acceptable salt, wherein:
Ring A is selected from optionally substituted ring of following one: phenyl, 8-10 unit aryl bicyclic ring, has independently selected from 1-4 heteroatomic 5-6 unit's monocycle hetero-aromatic ring of nitrogen, oxygen and sulphur and has the heteroatomic 8-10 of independently selected from nitrogen, oxygen and sulphur 1-4 unit two ring hetero-aromatic rings;
Ring B is an optionally substituted ring, this ring is selected from the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is the ring of the saturated or undersaturated monocyclic heterocycles of part of 1 to 2 heteroatomic 3-8 unit independently selected from nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur;
X is selected from O, S, N-CN and NR;
R is hydrogen or is a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, have independently selected from the 1-2 of nitrogen, oxygen and sulphur heteroatomic 3-8 unit saturated or the ring of undersaturated heterocycle partly, phenyl, and there is the heteroatomic 5-6 of independently selected from nitrogen, oxygen and sulphur 1-4 unit hetero-aromatic ring;
Y is covalent linkage or the C of substituted divalence optionally 1-4alkyl, wherein, a methylene unit of Y optionally by-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-substitute;
R 1and R 2be hydrogen independently of one another or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is 1-2 the ring independently selected from the saturated or undersaturated monocyclic heterocycles of part of the heteroatomic 3-8 unit of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
R 1and R 2and insert form together with the atom between them a kind of 1-3 of having heteroatomic 4-8 unit independently selected from nitrogen, oxygen and sulphur saturated, the ring of undersaturated or aromatic heterocycle partly, the ring quilt-(R wherein forming thus 5) preplace;
N, m and p are selected from an integer of 0,1,2,3 and 4;
Q is an integer, is selected from 0,1 and 2;
R 3, R 4, and R 5halogen ,-NO independently of one another 2,-CN ,-N 3,-L-R 6, or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, the ring of the saturated or undersaturated monocycle carbocyclic ring of part of 3-8 unit, phenyl, two cyclophane rings of 8-10 unit, there is 1-2 the ring independently selected from the saturated or undersaturated monocyclic heterocycles of part of the heteroatomic 3-8 unit of nitrogen, oxygen and sulphur, there is 1-4 the hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur, or:
Two R on ring B 3group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
Two R on ring A 4group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them; Or:
By R 1and R 2two R on the ring forming 5group and inserting forms saturated, the ring of undersaturated or aryl partly of a kind of 0-3 of having the heteroatomic 4-8 unit condensing independently selected from nitrogen, oxygen and sulphur together with the atom between them;
L is covalent linkage or the C of substituted divalence optionally 1-6alkyl, wherein, one or two methylene unit of L optionally and is independently substituted below :-Cy-,-O-,-S-,-N (R 6)-,-C (O)-,-C (S)-,-C (O) N (R 6)-,-N (R 6) C (O) N (R 6)-,-N (R 6) C (O)-,-N (R 6) C (O) O-,-OC (O) N (R 6)-,-S (O)-,-S (O) 2-,-S (O) 2n (R 6)-,-N (R 6) S (O) 2-,-OC (O)-or-C (O) O-;
-Cy-is an optionally substituted divalence ring, this ring is selected from the saturated or undersaturated ring alkenylene of the part ring of a 3-7 unit, one has 1-4 the saturated or undersaturated heterocycle alkylene of the part basic ring independently selected from the heteroatomic 4-7 unit of nitrogen, oxygen and sulphur, phenylene, one has 1-4 the heteroarylidene independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, the arylidene of two rings of a 8-10 unit, and one have 1-4 the heteroarylidenes independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; And
Each R 6be hydrogen independently or be a kind ofly selected from following optionally substituted group: C 1-6aliphatic group, phenyl, the ring of the saturated or undersaturated carbocyclic ring of part of 3-7 unit, two ring fillings of 8-10 unit, the ring of the carbocyclic ring of undersaturated or aryl partly, there is 1-4 the ring independently selected from the saturated or undersaturated heterocycle of part of the heteroatomic 4-7 unit of nitrogen, oxygen and sulphur, there is 1 to 4 hetero-aromatic ring independently selected from the monocycle of the heteroatomic 5-6 unit of nitrogen, oxygen and sulphur, and there are 1-4 the hetero-aromatic rings independently selected from two rings of the heteroatomic 8-10 unit of nitrogen, oxygen and sulphur; Or:
Two R on identical nitrogen 6and insert and form saturated, a undersaturated or aromatic heterocycle partly with 1-2 the heteroatomic 4-7 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them,
Its condition is that this compound is not (Z)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-N-cyclopentyl acrylamide, (Z)-1-(azetidin-1-yl)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) third-2-alkene-1-ketone, (Z)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-1-(3, 3-difluoro azetidin-1-yl) third-2-alkene-1-ketone, (Z)-1-(3, 3-difluoro azetidin-1-yl)-3-(3-(3-methoxyl group-5-(trifluoromethyl) phenyl)-1H-1, 2, 4-triazol-1-yl) third-2-alkene-1-ketone, (Z)-1-(3, 3-difluoro azetidin-1-yl)-3-(3-(3-isopropoxy-5-(trifluoromethyl) phenyl)-1H-1, 2, 4-triazol-1-yl) third-2-alkene-1-ketone, (Z)-3-(5-(3-chloro-phenyl-)-4H-1, 2, 4-triazole-3-yl)-N phenyl acrylamide, (Z)-3-(5-(3-chloro-phenyl-)-4H-1, 2, 4-triazole-3-yl)-N-methyl-N phenyl acrylamide, (E)-tertiary butyl (4-(3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) acrylamido) phenyl) carbamate, (E)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-N-(4-p-methoxy-phenyl) acrylamide, (E)-N-(3-chloro-phenyl-))-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) acrylamide, (E)-N-(4-aminophenyl))-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) acrylamide, (Z)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-N-sec.-propyl-N methacrylamide, (Z)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) the fluoro-NIPA of-N-, (Z)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) acrylamide, (E)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-N phenyl acrylamide, (E)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl)-N-methyl-N phenyl acrylamide, (E)-3-(3-(3-chloro-phenyl-)-1H-1, 2, 4-triazol-1-yl) acrylamide or (Z)-3-(3-(3-isopropoxy-5-(trifluoromethyl) phenyl)-1H-1, 2, 4-triazol-1-yl) acrylamide.
2. compound according to claim 1, wherein encircles A and is a kind of 1-4 of having the monocycle hetero-aromatic ring independently selected from the heteroatomic optionally substituted 5-unit of nitrogen, oxygen and sulphur.
3. compound according to claim 1, wherein encircles A and is selected from pyrryl, furyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl group.
4. compound according to claim 3, wherein encircling A is triazole.
5. compound according to claim 3, wherein encircling A is pyrryl.
6. compound according to claim 3, wherein encircling A is pyrazolyl.
7. compound according to claim 3, wherein encircling A is imidazolyl.
8. compound according to claim 3, wherein encircles A and is selected from following:
9. compound according to claim 1, wherein encircles A and is the monocycle hetero-aromatic ring of the optionally substituted 6-unit of a kind of 1-4 of having nitrogen-atoms.
10. compound according to claim 9, wherein encircles A and is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl and tetrazine base.
11. compounds according to claim 10, wherein encircling A is pyridyl.
12. according to the compound described in any one in claim 1-11, and wherein encircling B is phenyl.
13. compounds according to claim 12, wherein to encircle B be substituted and represented by following structural formula:
Figure FDA0000484103900000052
14. according to the compound described in any one in claim 1-13, and wherein X is O.
15. according to the compound described in any one in claim 1-14, and wherein Y is a kind of covalent linkage.
16. according to the compound described in any one in claim 1-15, wherein R 1and R 2and insert and form saturated, a ring for undersaturated or aromatic heterocycle partly with 1-3 the heteroatomic 4-8 unit independently selected from nitrogen, oxygen and sulphur together with the atom between them.
17. compounds according to claim 16, wherein by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is represented by following structural formula:
Figure FDA0000484103900000061
18. compounds according to claim 17, wherein p is 2.
19. compound according to claim 18, wherein R 5be-F.
20. compounds according to claim 19, wherein by R 1, R 2and the ring that inserts the saturated heterocycle of the 4-8 unit of the atom formation between them is represented by following structural formula:
Figure FDA0000484103900000062
21. compounds according to claim 1, wherein this compound is represented by following structural formula:
Figure FDA0000484103900000071
Or its a kind of pharmacy acceptable salt.
22. compounds according to claim 1, wherein this compound is by any expression in following structural formula, or its a kind of pharmacy acceptable salt:
Figure FDA0000484103900000072
Figure FDA0000484103900000081
Figure FDA0000484103900000091
Figure FDA0000484103900000101
Figure FDA0000484103900000111
Figure FDA0000484103900000121
Figure FDA0000484103900000131
Figure FDA0000484103900000141
23. compounds as claimed in claim 1, wherein this compound is represented by following structural formula:
Or its a kind of pharmacy acceptable salt.
24. 1 kinds of compounds that represented by structural formula (VI):
Figure FDA0000484103900000161
Or its a kind of pharmacy acceptable salt, wherein:
Z is selected from N, CH and C (Cl);
R 1hydrogen; And
R 2be selected from-CH 2-oxazoles-5-base ,-CH 2-pyrimidine-5-base ,-CH 2-(1-methylpyrrolidin-3-yl) or
Figure FDA0000484103900000162
or:
R 1and R 2form with together with the nitrogen-atoms of their combinations
Figure FDA0000484103900000163
Figure FDA0000484103900000164
4-hydroxy piperidine-1-base, pyrrolidin-1-yl or azetidin-1-base, wherein optionally and independently replaced by 2 substituting groups of as many as on this pyrrolidin-1-yl and the each comfortable 3-of azetidin-1-base position, and this substituting group is selected from fluorine ,-CF 3,-CH 3,-OH, pyridine-2-base ,-CH 2-N (CH 3) 2,-CH 2-NH-CH 3,-CH 2-NH 2,-CN ,-C (O)-O-CH 3; And
R 7be selected from fluorine ,-OH and-CF 3.
25. compounds according to claim 24, wherein this compound is by any expression in following structural formula, or its a kind of pharmacy acceptable salt:
Figure FDA0000484103900000171
Figure FDA0000484103900000181
26. 1 kinds of compositions, said composition comprises in claim 1-25 compound or its a kind of pharmacy acceptable salt described in any one, and a kind of pharmaceutically acceptable carrier, adjuvant or vehicle.
27. 1 kinds for regulating the method for CRM1, and the method comprises the compound described in any one in the claim 1-25 of CRM1 and treatment significant quantity or the composition described in claim 26 are contacted.
28. 1 kinds are used for the treatment of, regulate and/or disorderly method that prevention is associated with CRM1, and the method comprises the experimenter who the compound described in any one in the claim 1-25 for the treatment of significant quantity or the composition described in claim 26 is given it to have needs.
29. methods according to claim 28, wherein this disorder is selected from cancer, tumprigenicity disorder, diseases associated with inflammation, abnormal structure's growth, fibrotic disorders, kidney disorder, and virus infection.
30. according to a kind of compound described in any one in claim 1-25 or its a kind of pharmacy acceptable salt, for having the experimenter's who needs the one disorder relevant to CRM1 activity to use in treatment to it.
31. according to a kind of compound described in any one in claim 1-25 or its a kind of pharmacy acceptable salt manufacturing a kind of being used for the treatment of and purposes in the active relevant disorderly medicine of CRM1.
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